This invention relates to a novel method for the treatment and/or prophylaxis of conditions associated with a need for inhibition of glycogen synthase kinase-3 (GSK-3), especially diabetes, including chronic neurodegenerative conditions, including dementias such as Alzheimer""s disease, neurotraumatic diseases, such as acute stroke, mood disorders such as schizophrenia and manic depression, and for the treatment and/or prophylaxis of hair loss and cancer, and to certain novel inhibitors of GSK-3 for use in such a method.
GSK-3 is a serine/threonine protein kinase composed of two isoforms (xcex1 and xcex2) which are encoded by distinct genes. GSK-3 is one of several protein kinases which phosphorylates glycogen synthase (GS) (Embi et al Eur. J. Biochem. (107) 519-527 (1980)). The xcex1 and xcex2 isoforms have a monomeric structure of 49 and 47 kD respectively and are both found in mammalian cells. Both isoforms phosphorylate muscle glycogen synthase (Cross et al Biochemical Journal (303) 21-26 (1994)) and these two isoforms show good homology between species (e.g. human and rabbit GSK-3xcex1 are 96% identical).
Type II diabetes (or Non-Insulin Dependent Diabetes Mellitus, NIDDM) is a multifactorial disease. Hyperglycaemia is due to insulin resistance in the liver, muscle and other tissues coupled with inadequate or defective secretion of insulin from pancreatic islets. Skeletal muscle is the major site for insulin-stimulated glucose uptake and in this tissue, glucose removed from the circulation is either metabolised through glycolysis and the TCA cycle, or stored as glycogen. Muscle glycogen deposition plays the more important role in glucose homeostasis and Type II diabetic subjects have defective muscle glycogen storage.
The stimulation of glycogen synthesis by insulin in skeletal muscle results from the dephosphorylation and activation of glycogen synthase (Villar-Palasi C. and Lamer J. Biochim. Biophys. Acta (39) 171-173 (1960), Parker P J et al. Eur. J. Biochem. (130) 227-234 (1983), and Cohen P. Biochem. Soc. Trans. (21) 555-567 (1993)). The phosphorylation and dephosphorylation of GS are mediated by specific kinases and phosphatases. GSK-3 is responsible for phosphorylation and deactivation of GS, while glycogen bound protein phosphatase 1 (PP1G) dephosphorylates and activates GS. Insulin both inactivates GSK-3 and activates PP1G (Srivastava A K and Pandey S K Mol. and Cellular Biochem. (182) 135-141 (1998)).
Chen et al. Diabetes (43) 1234-1241 (1994) found that there was no difference in the mRNA abundance of PP1G between patients with Type II diabetes and control patients, suggesting that an increase in GSK-3 activity might be important in Type II diabetes. It has also recently been demonstrated that GSK-3 is overexpressed in Type II diabetic muscle and that an inverse correlation exists between skeletal muscle GSK-3xcex1 activity and insulin action (Nikoulina et al Glycogen Synthase Kinase-3 in Human Skeletal Muscle: Relationship To Insulin Resistance in Type II Diabetes. Diabetes (47(1)) 0028 Page A7 (1998) (Oral presentation)). Overexpression of GSK-3xcex2 and constitutively active GSK-3xcex2 (S9A, S9E) mutants in HEK-293 cells resulted in supression of glycogen synthase activity (Eldar-Finkelman et al., PNAS (93) 10228-10233 (1996)) and overexpression of GSK-3xcex2 in CHO cells, expressing both insulin receptor and insulin receptor substrate 1 (IRS-1), resulted in an impairment of insulin action (Eldar-Finkelman and Krebs PNAS (94) 9660-9664 (1997)). Recent evidence for the involvement of elevated GSK-3 activity and the development of insulin resistance and type II diabetes in adipose tissue has emerged from studies undertaken in diabetes and obesity prone C57BL/6J mice (Eldar-Finkelman et al., Diabetes (48) 1662-1666 (1999)).
GSK-3 has been shown to phosphorylate other proteins in vitro including the eukaryotic initiation factor eIF-2B at Serine540 (Welsh et al., FEBS Letts (421) 125-130 (1998)). This phosphorylation results in an inhibition of eIF-2B activity and leads to a reduction in this key regulatory step of translation. In disease states, such as diabetes, where there is elevated GSK-3 activity this could result in a reduction of translation and potentially contribute to the pathology of the disease.
Several aspects of GSK-3 functions and regulation in addition to modulation of glycogen synthase activity indicate that inhibitors of this enzyme may be effective in treatment of disorders of the central nervous system. GSK-3 activity is subject to inhibitory phosphorylation by PI 3 kinase-mediated or Wnt-1 class-mediated signals that can be mimicked by treatment with lithium, a low mM inhibitor of GSK-3 (Stambolic V., Ruel L. and Woodgett J. R Curr. Biol. 1996 6(12): 1664-8).
GSK-3 inhibitors may be of value as neuroprotectants in treatment of acute stroke and other neurotraumatic injuries. Roles for PI 3-kinase signalling through PKB/akt to promote neuronal cell survival are well established, and GSK-3 is one of a number of PKB/akt substrates to be identified that can contribute to the inhibition of apoptosis via this pathway (Pap and Cooper, (1998) J. Biol. Chem. 273: 19929-19932). Evidence suggests that astrocytic glycogen can provide an alternative energy source to facilitate neuronal survival under conditions of glucose deprivation (for example see Ransom, B. R. and Fern, R. (1997) Glia 21: 134-141 and references therein). Lithium is known to protect cerebellar granule neurons from death (D""Mello et al., (994) Exp. Cell Res. 211: 332-338 and Volonte et al (1994) Neurosci. Letts. 172: 6-10) and chronic lithium treatment has demonstrable efficacy in the middle cerebral artery occlusion model of stroke in rodents (Nonaka and Chuang, (1998) Neuroreport 9(9): 2081-2084). Wnt-induced axonal spreading and branching in neuronal culture models has been shown to correlate with GSK-3 inhibition (Lucas and Salinas. (1997) Dev. Biol. 192: 31-44) suggesting additional value of GSK-3 inhibitors in promoting neuronal regeneration following neurotraumatic insult.
Tau and xcex2-catenin, two known in vivo substrates of GSK-3, are of direct relevance in consideration of further aspects of the value of GSK-3 inhibitors in relation to treatment of chronic neurodegenerative conditions. Tau hyperphosphorylation is an early event in neurodegenerative conditions such as Alzheimer""s disease (AD), and is postulated to promote microtubule disassembly. Lithium has been reported to reduce the phosphorylation of tau, enhance the binding of tau to microtubules, and promote microtubule assembly through direct and reversible inhibition of glycogen synthase kinase-3 (Hong M., Chen D. C., Klein P. S. and Lee V. M. J. Biol. Chem. 1997 272(40) 25326-32). xcex2-catenin is phosphorylated by GSK-3 as part of a tripartite complex with axin, resulting in xcex2-catenin being targetted for degradation (Ikeda el al., (1998) EMBO J. 17: 1371-1384). Inhibition of GSK-3 activity is a key mechanism by which cytosolic levels of catenin are stabilised and hence promote xcex2-catenin-LEF-1/TCF transcriptional activity (Eastman, Grosschedl (1999) Curr. Opin. Cell Biol. 11: 233). Rapid onset AD mutations in presenilin-1 (PS-1) have been shown to decrease the cytosolic xcex2-catenin pool in transgenic mice. Further evidence suggests that such a reduction in available xcex2-catenin may increase neuronal sensitivity to amyloid mediated death through inhibition of xcex2-catenin-LEF-1/TCF transcriptional regulation of neutoprotective genes (Zhang et al., (1998) Nature 395: 698-702). A likely mechanism is suggested by the finding that mutant PS-1 protein confers decreased inactivation of GSK-3 compared with normal PS-1 (Weihl, C. C., Ghadge, G. D., Kennedy, S. G., Hay, N., Miller, R. J. and Roos, R. P.(1999) J. Neurosci. 19: 5360-5369).
WO 97/41854 (University of Pennsylvania) discloses that an effective drug for the treatment of manic depression is lithium but that there are serious drawbacks associated with this treatment. Whilst the precise mechanism of action of this drug for treatment of manic depression remains to be fully defined, current models suggest that inhibition of GSK-3 is a relevant target that contributes to the modulation of AP-1 DNA binding activity observed with this compound (see Manji et al., (1999) J. Clin. Psychiatry 60 (suppl 2): 27-39 for review).
GSK-3 inhibitors may also be of value in treatment of schizophrenia. Reduced levels of xcex2-catenin have been reported in schizophrenic patients (Cotter D, Kerwin R, al-Sarraji S, Brion J P, Chadwich A, Lovestone S, Anderton B, Everall I, 1998 Neuroreport 9:1379-1383) and defects in pre-pulse inhibition to startle response have been observed in schizophrenic patients (Swerdlow et al., (1994) Arch. Gen. Psychiat. 51: 139-154). Mice lacking the adaptor protein dishevelled-1, an essential mediator of Wnt-induced inhibition of GSK-3, exhibit both a behavioural disorder and defects in pre-pulse inhibition to startle response (Lijam N, Paylor R, McDonald M P, Crawley J N, Deng C X, Herrup K, Stevens K E, Maccaferri G, McBain C J, Sussman DJ, Wynshaw-Boris A. (1997) Cell 90: 895-905). Together, these findings implicate deregulation of GSK-3 activity as contributing to schizophrenia. Hence, small molecule inhibitors of GSK-3 catalytic activity may be effective in treatment of this mood disorder.
The finding that transient xcex2-catenin stabilisation may play a role in hair development (Gat el al., Cell (95) 605-614(1998)) suggests that GSK-3 inhibitors could be used in the treatment of baldness.
Certain substitued 3-amino-4-arylmaleimides are disclosed in Tetrahedron (1998), 54(9), 1745-1752; Liebigs Annalen 1894, 282, 81; BE 659639; J Amer Chem Soc 1958, 80, 1385; J. Prakt. Chem. (1979), 321(5), 787-96; Eur. J. Org. Chem. (1998), (7), 1467-1470; Chem. Heterocycl. Compd. (N.Y.) (1997), 33(1), 69-73; J. Prakt. Chem. (1987), 329(4), 587-91; Collect, Czech. Chem. Commun. (1985), 50(6), 1305-11; Tetrahedron (1984), 40(18), 3499-502; J. Prakt. Chem. (1983), 325(2), 293-300; J Prakt Chem 1983, 325 (2) 293-300; Tetrahedron (1980), 36, 1801-5; which compounds have no disclosed pharmaceutical utility.
Certain 3-amino-4-arylmaleimides are disclosed in Bioorg. Med. Chem. Lett. (1995), 5(1), 67-72; J. Med. Chem. (1992), 35(1), 177-84; Tetrahedron Lett. (1990), 31(36), 5201-4; EP 328026; Bioorg. Med. Chem. Lett. (1994), 4(24), 2845-50, which compounds are disclosed as being protein kinase C inhibitors or trypanothione reductase inhibitors. Certain 3-amino-4-arylmaleimides are disclosed in DE 4005969 and DE 4005970 as having activity as anti-allergics and immunotherapeutics.
U.S. Pat. No. 3,335,147 discloses certain 3-amino-4-arylmaleimides as having topical anaesthetic activity. DE 19744257 discloses certain 3-amino-4-arylmaleimides as being tyrosine kinase inhibitors. Chem. Pharm. Bull. (1998), 46(4), 707-710 discloses certain 3-amino-4-arylmaleimides as being trypanothione reductase inhibitors. SA 672268 discloses certain 3-amino-4-arylmaleimides as being antimicrobials.
None of the above mentioned references discloses that the 3-amino-4-arylmaleimides possess GSK-3 inhibitor activity.
We have now discovered that a series of certain 3-amino-4-arylmaleimides are particularly potent and selective inhibitors of GSK-3. These compounds are indicated to be useful for the treatment and/or prophylaxis of conditions associated with a need for inhibition of GSK-3, such as diabetes, chronic neurodegenerative conditions, including dementias such as Alzheimer""s disease, manic depression, mood disorders, such as schizophrenia, neurotraumatic diseases, such as acute stroke, hair loss, and cancer. Certain of these compounds are novel and such compounds comprise a further aspect of the invention. In addition, as indicated above it is considered that GSK-3 inhibitors per se are potentially useful in the treatment and/or prophylaxis of mood disorders, such as schizophrenia, neurotraumatic diseases, such as acute stroke, and for the treatment and/or prophylaxis of cancer and hair loss.
Accordingly, in a first aspect, the present invention provides a method for the treatment of conditions associated with a need for inhibition of GSK-3, such as diabetes, dementias such as Alzheimer""s disease and manic depression which method comprises the administration of a pharmaceutically effective, non-toxic amount of a compound of formula (I): 
or a pharmaceutically acceptable derivative thereof, wherein:
R is hydrogen, alkyl, aryl, or aralkyl:
R1 is hydrogen, alkyl, aralkyl, hydroxyalkyl or alkoxyalkyl;
R2 is substituted or unsubstituted aryl or substituted or unsubstituted hetcrocyclyl;
R3 is hydrogen, substituted or unsubstituted alkyl, cycloalkyl, alkoxyalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl or aralkyl wherein the aryl moiety is substituted or unsubstituted; or,
R1 and R3 together with the nitrogen to which they are attached form a single or fused, optionally substituted, saturated or unsaturated heterocylic ring;
to a human or non-human mammal in need thereof.
Suitably, R is hydrogen, C1-6alkyl, such as methyl or ethyl, or R is phenyl or benzyl.
Preferably, R is hydrogen.
Suitably, R1 is hydrogen, C1-6alkyl, such as methyl, ethyl, or R1 is hydroxyethyl or methoxyethyl.
Preferably, R1 is hydrogen.
When R2 is substituted or unsubstituted aryl, examples of aryl groups include phenyl and naphthyl.
When R2 is substituted or unsubstituted heterocyclyl, examples of heterocyclyl groups include indolyl, benzofuranyl, thienyl and benzothienyl.
When R2 is substituted phenyl, suitable substituents include up to three groups independentdy selected from halo, C1-6alkoxy, nitro, perfluoroC1-6alkyl, benzoyl, C1-6alkoxycarbonyl, C1-6alkylsulphonyl, hydroxy, xe2x80x94O(CH2)wOxe2x80x94 where w is 1 to 4, phenoxy, benzyloxy, C1-6alkoxyC1-6alyl, perfluoroC1-6alkoxy, C1-6alkylSxe2x80x94, perfluoroC1-6alkylSxe2x80x94, (diC1-6alkyl)Nxe2x80x94, amino, C1-6alkylcarbonylamino, substituted or unsubstituted ureido, phenylcarbonylamino, benzylcarbonylamino, styrylcarbonylamino, (diC1-6alkoxy)(phenyl)Cxe2x80x94, C alkyl, and phenyl. Suitable substituents for ureido include fluorophenyl, phenylC1-6alkyl-, cyclohexyl, C1-6alkenyl, C1-6alkyl, and C1-6alkoxyphenyl.
When R2 is substituted indolyl, suitable substituents include C1-6alkyl.
When R2 is substinned benzothienyl, suitable substiuents include C1-6alkyl.
Suitably, R2 is substituted or unsubstituted phenyl.
Favourably, R2 is phenyl substituted with;
4-Cl: 3-Cl: 2-Cl: 2,4-di-Cl; 3,4-di-Cl: 3,5-di-Cl; 2,6-di-Cl; 2-F-6-Cl; 2-F; 3-F; 2,3-di-F; 2,5-di-F; 2,6-di-F; 3,4-di-F; 3,5-di-F; 2,3,5-tri-F; 3,4,5-tri-F; 2-Br; 3-Br; 4-Br; 2-I; 4-I; 3-Cl-4-OMe; 3-NO2-4-Cl; 2-OMe-5-Br, 2-NO2; 3-NO2; 2-CF3; 3-CF3; 4-CF3; 3,5-di-CF3; 4-PhC(O); 4-MeO(O)Cxe2x80x94; 4-MeSO2xe2x80x94; 4-OH; 2-OMe; 3-OMe; 4-OMe; 2,4-di-OMe; 2,5-di-OMe; 3,4-di-OMe; 3,4-OCH2Oxe2x80x94; 3,4,5-tri-OMe; 3-NO2-4-OMe; 4-OnBu; 2-OEt; 2-OPh; 3-OPh; 4-OPh; 2-OCH2Ph; 4-OCH2Ph; 4-(MeOCH2); 2-OCF3; 4-OCF3; 4-SMe; 3-SCF3; 4-NMe2; 3-NH2; 3-(NHC(O)Me); 3-[NHC(O)NH(3-F-Ph)]; 3-[NHC(O)NH(CH2)2Ph]; 3-[NHC(O)NHCyclohexyl]; 3-[NHC(O)NHCH2CHxe2x95x90CH2]; 3-[NHC(O)Ph]; 3-[NHC(O)CH2Ph]; 3-[trans-NHC(O)CHxe2x95x90CHPh]; 3-[NHC(O)nPr]; 3-[NHC(O)NHEt]; 3-[NHC(O)NH(3-OMe-Ph)]; 4-[C(OMe)2Ph]; 2-Me: 3-Me; 4-Me; 4-iPr; 2,5-di-Me; 3,5-di-Me, 4-Ph, 2,3-[(xe2x80x94CH2xe2x95x90CH2xe2x80x94)], or 3,4-[(xe2x80x94CH2xe2x95x90CH2xe2x80x94)].
When R3 is alkyl, examples include methyl and ethyl.
When R3 is cycloalkyl, examples include cyclohexyl.
When R3 is alkoxyalkyl, examples include methoxyethyl.
When R3 is aralkyl, examples include benzyl and phenylethyl.
When R3 is substituted or unsubstituted aryl, examples include fluorenyl, phenyl, and dibenzofuryl.
When R3 is substituted or unsubstituted heterocyclyl, examples include thienyl, oxazolyl, benzoxazolyl, pyridyl, and pyrimidinyl.
When R1 and R3 together with the nitrogen atom to which they are attached form a fused heterocyclic ring, which ring may be unsubstituted or substituted, examples include indolinyl, indolyl, oxindolyl, benzoxazolinonyl, tetahydroquinolinyl, tetrahydroisoquinolinyl, benzimidazolyl, benzazepinyl, isoindolin-2-yl, and 1,3,3-trimethyl-6-azabicyclo[3,2,1]oct-6-yl.
When R1 and R3 together with the nitrogen atom to which they are attached form a single heterocyclic ring, which ring may be unsubstituted or substituted, examples include 1-phenyl-1,3,8-triazaspiro-[4,5]-decan-4-one-8-yl, piperazinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, and a pyridiniun ring.
When R3 is substituted phenyl, suitable substituents include up to three groups independently selected from substituted or unsubstituted C1-6alkyl, phenyl, benzyl, substituted or unsubstituted C1-6alkylSxe2x80x94, halo, hydroxy, substituted or unsubstituted C1-6alkoxy, substituted or unsubstituted phenoxy, indolyl, naphthyl, carboxy, C1-6alkoxycarbonyl, benzyloxy, pentafluorophenoxy, nitro, N-substituted or unsubstituted carbamoyl, substituted or unsubstituted C1-6alkycarbonyl, berzoyl, cyano, perfluoroC1-6alkylSO2xe2x80x94, C1-6alkylNHSO2xe2x80x94, oxazolyl, C1-6alkylcarbonylpiperazinyl, substituted or unsubstituted phenylSxe2x80x94, C1-6alkylpiperazinyl-, cyclohexyl, adamantyl, trityl, substituted or unsubstituted C1-6alkenyl, perfluoroC1-6alkyl, perfluoroC1-6alkoxy, perfluoroC1-6alkylSxe2x80x94, aminosulphonyl, alkylaminosulphonyl, dialkylaminosulphonyl, arylaminosulphonyl, morpholino, (diC1-6alkyl)amino, C1-6alkylCONHxe2x80x94, (diC1-6alkoxy)phenyl(CH2)nNHC(O)CH(phenyl)Sxe2x80x94 where n is 1 to 6, and C1-6alkylCON(C1-6alkyl)xe2x80x94, thiazolidinedionylC1-6alkly, phenylCH(OH)xe2x80x94, substituted or unsubstituted piperazinylC1-6alkoxy, substituted or unsubstituted benzoylamino: or xe2x80x94[CHxe2x95x90CHxe2x80x94C(O)O]xe2x80x94, xe2x80x94[(CHxe2x95x90CH)2]xe2x80x94, xe2x80x94[(CH2)xN(C1-6alkylcarbonyl)]xe2x80x94, xe2x80x94(CH2)xxe2x80x94, xe2x80x94SCHxe2x95x90Nxe2x80x94, xe2x80x94SC(C1-6alkyl)xe2x95x90Nxe2x80x94, xe2x80x94OCF2Oxe2x80x94, xe2x80x94CHxe2x95x90Nxe2x80x94NHxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94NHxe2x80x94, xe2x80x94OC(NHC1-6alkyl)xe2x95x90Nxe2x80x94, xe2x80x94OC(O)NHxe2x80x94, xe2x80x94C(O)NC1-6alkylC(O)xe2x80x94, xe2x80x94[CHxe2x95x90CHxe2x80x94CHxe2x95x90N]xe2x80x94, xe2x80x94[CHxe2x95x90C(C1-6alkylcarbonyl)O]xe2x80x94, xe2x80x94C(O)NHC(O)xe2x80x94, xe2x80x94[(CH2)xC(O)]xe2x80x94, xe2x80x94Nxe2x95x90Nxe2x80x94NHxe2x80x94, xe2x80x94Nxe2x95x90C(C1-6alkyl)Oxe2x80x94, xe2x80x94O(CH2)xOxe2x80x94. xe2x80x94(CH2)xSO2(CH2)yxe2x80x94, xe2x80x94N(C1-6alkylcarbonyl)(CH2)xxe2x80x94 where x and y are independently 1 to 4, pyrimidin-2-yloxy, phenylamino, N-[pyrimidin-2-yl]-N-[C1-6alkyl]amino, C1-6alkylsulphonylamino, and 1,2,3-thiadiazolyl.
Suitable substituents for C1-6alkyl include hydroxy, carboxy, unsubstituted or N-substituted carbonyl, N-morpholinylcarbonyl, C1-6alkylaminocarbonyl, fluoro, cyano, C1-6alkyl, C1-6alkoxycarbonylamino, amino, C1-6alkylcarbonylamino, benzoylamino, phenylaminocarbonylamino, C1-6alkoxycarbonyl, phosphono. mono-or bisC1-6alkylphosphonate, C1-6alkylaminosulphonyl, and C1-6alkylcarbonylaminoC1-6alkylaminoCOxe2x80x94,
Suitable substituents for C1-6alkylSxe2x80x94 include carboxy, C1-6alkoxycarbonyl, C1-6alkoxyC1-6alkylaminocarbonyl, unsubstituted or N-substituted carbamoyl, and fluoro.
Suitable substituents for C1-6alkoxy include C1-6alkoxy, phenyl, carboxy, C1-6alkoxycarbonyl, unsubstituted or N-substituted carbamoyl, and phenyl.
Suitable substituents for carbamoyl include C1-6alkyl, and C1-6alkoxyC1-6alkyl.
Suitable substituents for C1-6alkylcarbonyl include carboxy, and C1-6alkoxycarbonyl.
Suitable substituents for phenylSxe2x80x94 include chloro, nitro, carboxy, C1-6alkylaminocarbonyl, unsubstituted or N-substituted carbamoyl, and C1-6alkoxycarbonyl.
Suitable substituents for C1-6alkenyl include (diC1-6alkyl)aminocarbonyl, carboxy, C1-6alkoxycarbonyl, carbamoyl, and phenyl.
Suitable substituents for piperazinylC1-6alkoxy include methyl.
Suitable substituents for phenoxy include chloro.
Suitable substiments for benzoylamino include hydroxy.
When R3 is substituted benzofuryl, suitable substituents include C1-6alkylcarbonyl.
When R3 is substituted thienyl, suitable substituents include C1-6alkylcarbonyl.
When R3 is substituted oxazolyl, suitable substituents include C1-6alkyl.
When R3 is substituted benzoxazolyl, suitable substituents include halo.
When R3 is substituted pyridyl, suitable substituents include up to three substituents independently selected from C1-6alkyl, C1-6alkoxy, and halo.
Suitably, R3 is substituted or unsubstituted phenyl.
Favourably, R3 is phenyl substituted with;
2-Me: 2-Et; 2-iPr; 2-CH2OH; 2-Ph; 2-CH2Ph; 2-SMe; 2-F; 2-Cl; 2-OH; 2-OMe; 2-OPh; 2-Me-5-F; 2-Me-3-Cl; 2-Me-4-Cl; 2-Me-5-Cl; 2-Me-3-Br; 2,3-di-Me; 2,4-di-Me; 2-Me-4OH; 2-Me-4-OMe; 2-Me-5-CH2OH; 2,4,6-tri-Me; 2-(2-Indolyl); (1-Naphthyl); 2-Me-5-COOH; 2-Me-5-COOMe; 2-OH-5-COOH; 2-[O(CH2)2OMe]-5-[(CH2)2COOH]; 2-[SCH(Ph)CONH(CH2)2(3,4-di-OMePh)]; 3-Me; 3-Et; 3-CH2OH; 3-CH2OH-6-Me; 3-CH2OH-4-OMe; 3-CH2NMe2)-4-OMe; 3-[CH2COOH]; 3-[CH2COOMe]; 3-[CH2CONH2]; 3-[CH2CONHMe]; 3-[CH2-(thiazolidine-2,4-dion-5-yl)]: 3-SMe; 3-F; 3-Cl; 3-Br; 3-I; 3-CF3; 3-OH; 3-OMe; 3-OCH2Ph; 3-O-pentafluorophenyl; 3-(OCH2CO2H); 3-(OCH2CO2Me); 3-(OCH2CO2Et); 3-NO2; 3-CO2H; 3-CO2Me; 3-CONH2; 3-CONHMe; 3-CONHCH2CH2OMe; 3-COMe; 3-COPh; 3-(COCH2CH2CO2H); 3-(COCH2CH2CO2Me); 3-CN; 3-SO2CF3; 3-SO2NH-nBu; 3-(5-oxazolyl); 3-[4-methylpiperazin-1-yl]OMe; 3-[O-(pyrimidin-2-yl)]; 3-OH-4-OMe; 3,4-di-OMe; 3,5-di-OMe; 3,4-di-Me; 3,5-di-Me; 3-[trans-CHxe2x95x90CHCONMe2]-4-Cl; 3-F-4-Me; 3-Cl-4-Me; 3-Br-4-Me; 3,5-di-F; 3,4-di-Cl; 3,5-di-Cl; 3,5-di-Br; 3-Cl-4-Br; 3-Cl-4-I; 3-Cl-4-OH; 3-Br-4-OH; 3-F-4-OMe; 3-Cl-4-OMe; 3-Cl-4-SMe; 3-Br-4-Cl: 3-Br-4-OCF3; 3-Br-5-CF3; 3,5-di-Cl-4-OH; 3,5-di-Br-4-OH; 3,5-di-Cl-4-Me; 3,5-di-Br-4-Me: 3-[CH2CH(Me)CO2H]; 3-CO2H-4-Cl; 3-CO2Me-4-Cl; 3-CO2H-4-OH; 3-CO2CONH2-4-Me; 3-NO2-4-OH; 3-CO2H-4-SPh; 3-CO2H-4-[S-(2-CO2H-Ph)]; 3-CO2H-4-[S-(2-CONHMe-Ph)]; 3-CO2Et-4-[S-(2-CO2Et-Ph)]; 3-CO2H-4-[S-(3-CO2H-Ph)]; 3-CO2Me-4-[S-(4-Cl-Ph)]; 4-[N(Me)(Pyrimidin-2-yl)]; 4-Me; 4-nBu; 4-tBu; 4-Cyclohexyl; 4-Adamantyl; 4-CPh3; 4-CH2CN; 4-CH(OH)Me; 4-CH(OMe)Me; 4-CH2OH; 4-CH2NHC(O)t-Bu; 4-CH2NH2; 4-CH2NHCOMe; 4-CH2NHCOPh; 4-CH2NHCONHPh; 4-CH2CO2H; 4-CH2CO2Me; 4-[CH2P(O)(OH)2]; 4-[CH2P(O)(OEt)2]; 4-[CH2SO2NHMe]; 4-(CH2)2OH: 4-(CH2)2NH2; 4-(CH2)2NHCOPh; 4-(CH2)2NHC(O)Ot-Bu; 4-[(CH2)2CO2H); 4-[(CH2)2CO)Me]; 4-(CH2CH2CONH2); 4-[CH2CH2CONH(CH2)6NHCOMe]; 4-[(CH2)3CO2H]; 4-[(CH2)3CO2Me]; 4-[CHxe2x95x90CH2]; 4-(CHxe2x95x90CHCO2H); 4-(CHxe2x95x90CHCO2Et); 4-(CHxe2x95x90CHCONH2); 4-(CHxe2x95x90CHPh); 4-(CHxe2x95x90CH(4-OHPh)); 4-[1,2,3-thiadiazol-4-yl]; 4-[OCH2-(1-methyl-piperazn-4-yl)]; 4-[4-methylpiperazin-1-yl]; 4-CF3; 4-SMe: 4-(SCH2CO2H); 4-(SCH2CO2Me); 4-[SCH2CONH(CH2)2OMe]; 4-SCF3; 4-[S-(4-NO2-Ph)]; 4-[S-(2-CO2H-Ph)]; 4-[S-(3-CO2H-Ph)]; 4-SO2NH2; 4-F; 4-Cl; 4-Br; 4-OH; 4-OMe: 4-OnBu; 4-OPh; 4-[O-(4-Cl-Ph)]; 4-OCH2Ph; 4-OCH2CO2Me; 4-COPh; 4-COMe; 4-CONH2; 4-CO2H; 4-CN; 4-NO2; 4-morpholinyl; 4-[CH2CO-morpholin-1-yl)]; 4-[CH2CONH(CH2)2OMe]; 4-[(CH2)2CONH(CH2)6NHC(O)Ot-Bu]; 4-[(CH2)2CONH(CH2)6NH2]; 4-[(CH2)2CONH(CH2)6NH-biotinyl]; 4-NMe2; 4-NHCOMe; 4-N(Me)COMe, 2,3-di-F; 4-[NHCO(Ph-2-OH)], 4-(phenylamino); 4-methylsulphonylamino, 2,4-di-F; 2,5-di-F; 2-OMe-3-F; 3-CH2OMe; 3-CH(OH)Ph; 3,4-di-F; 3-CO2H-4-CH2CO2H; 3-CO2H-4-[S-(2-CO2Et)Ph]; 3-CO2Et-4-[S-(4-CO2H)Ph]; 3-CONHMe-4-[S-(2-CONHMe)-Ph]; 3-[4-dichloroacetyl)piperazin-1-yl]-4-OMe; 4-CH2CONH2; 4-SPh; 4-[S-(4-CO2H-Ph)]; and 4-OCH2CO2H.
When R1 and R3 together with the nitrogen, atom to which they are attached form indolinyl, suitable substituents include C1-6alkyl, perfluoroC1-6alkyl, C1-6alkylSO2NH-hydroxyC1-6alkyl, carboxy, C1-6alkoxycarbonyl, C1-6alkoxy, halo, t-butoxycarbonylpiperazin-1-yl, 4-(C1-6alkyl)piperazinyl, piperazinyl, amido, and nitro.
When R1 and R3 together with the nitrogen atom to which they are attached form piperazinyl, suitable substituents include alkylcarbonyl, alkyl, or aryl.
When R1 and R3 together with the nitrogen atom to which they are attached form tetrahydroquinolinyl, suitable substituents include perfluoroC1-6alkyl.
When R1 and R3 together with the nitrogen atom to which they are attached form a pyridinium ring, suitable substituents include amino.
When R1 and R3 together with the nitrogen atom to which they are attached form pyrrolidinyl, suitable substituents include hydroxy.
When R1 and R3 together with the nitrogen atom to which they are attached form piperidinyl, suitable substituents include benzyl, hydroxyC1-6alkyl, C1-6alkyl, hydroxy, carbamoyl, and C1-6alkoxycarbonyl.
When R1 and R3 together with the nitrogen atom to which they are attached form oxindolyl, suitable substituents include C1-6alkyl.
There is a sub-group of compounds, falling wholly within formula (I), and being of formula (IA), wherein R, R1, R2 and R3 are as defined in relation to formula (I), with the proviso that formula (IA) does not include the following compounds, hereinafter referred to as List A:
3-phenyl-4-(4-methylpiperazino)-pyrrale-2,5-dione;
3-[4-diphenylmethyl)-1-piperazinyl]-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;
3-phenyl-4-(4-phenylpiperazino)-pyrrole-2,5-dione;
1-methyl-3-phenyl-4-(4-phenylpiperazino)-pyrrole-2,5-dione;
1-ethyl-1-phenyl-4-(4-chlorophenylpiperazino)-pyrrole-2,5-dione;
1-allyl-3-phenyl-4-(4-methylpiperazino)pyrrole-2,5-dione;
3-indol-1-yl-4-(1-methyl-1H-indol-3-yl)-pyrrole-2,5-dione;
1-(1-methyl-2,5-dioxo-4-phenylamino-2,5-dihydro-1H-pyrrol-3-yl)pyridinium chloride;
1-[1-(4-methyl-pentyl)-2,5-dioxo-4-phenylamino-2,5-dihydro-1H-pyrrol-3-yl]pyridinium chloride;
1-(1-dodecyl-2,5-dioxo-4-phenylamino-2,5-dihydro-1H-pyrrol-3-yl)-pyridinium chloride;
3-[2-benzo[b]thien-2-yl-3-[4-(dimethylamino)-2,5-dihydro-2,5-dioxo-1H-pyrrol-3-yl]-1H-indol-1-yl]-carbamimidothioic acid, propyl ester;
3-(dimethylamino)-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;
3-(1H-indol-3-yl)-1-methyl-4(phenylamino)-1H-pyrrole-2,5-dione;
3-(1H-indol-3-yl)-1-methyl-4-([[4-(trifluoromethyl)phenyl]amino]-1H-pyrrole-2,5-dione;
3-(1H-indol-3-yl)-1-methyl-4-(methylamino)-1H-pyrrole-2,5-dione;
3-(1H-imidazo[4,5-b]pyridin-1-yl)-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;
3-(6-chloro-9H-purin-9-yl)-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;
3-(6-amino-9H-purin-9-yl)-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;
3-(1H-indol-3-yl)-1-methyl-4-(1H-pyrrolo[2,3-b]pyridin-1-yl)-1H-pyrrole-2,5-dione;
3-(1H-indol-3-yl)-1-methyl-4-(1-piperidinyl)-1H-pyrrole-2,5-dione;
1-acetyl-3-[2,5-dihydro-1-methyl-2,5-dioxo-4-[[4-(trifluoromethyl)phenyl]amino]-1H-pyrrol-3-yl]-1H-indole;
3-(1H-benzimidazol-1-yl)-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;
3-(1H-benzotriazol-1-yl)-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;
3-(1H-imidazol-1-yl)-4-1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;
3-(1H-indol-1-yl)-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;
3-(1H-indazol-1-yl)-4-1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;
3-(3-[(dimethylamino)methyl]-1H-indol-1-yl]-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;
3-(1H-benzimidazol-1-yl)-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;
3-(1H-indol-1-yl)-4-(1-methyl-1H-indol-3-yl) 1H-pyrrole-2,5-dione;
3-amino-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;
3-amino-4-(5-methoxy-1H-indol-3-yl)-1H-pyrrole-2,5-dione;
1H-Indole-1-carboxylic acid, 3-(4-amino-2,5-dihydro-1-methyl-2,5-dioxo-1H-pyrrol-3-yl)-, 1,1-dimethylethyl ester;
3-(1H-indol-3-yl)-1-methyl-4-[(phenylmethyl)amino]-1H-pyrrole-2,5-dione;
Gylcine, N-[2,5-dihydro-4-(1H-indol-3-yl)-1-methyl-2,5-dioxo-1H-pyrrol-3-yl]-, ethyl ester;
3-amino-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;
3-[[3[(3-aminopropyl)amino]propyl]amino]-4-1H-indol-3-yl)-1H-pyrrole-2,5-dione;
[[3-[4-(3-aminopropyl)-1-piperazinyl]propyl]amino]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;
3-(1H-indol-3-yl)-4-[[3-(4-methyl-1-piperazinyl)propyl]amino]-1H-pyrrole-2,5-dione;
1-[3-[(3-aminopropyl)amino]propyl]-3-[[3-[(3-aminopropyl)amino]propyl]amino]-4-1H-indol-3-yl)-1H-pyrrole-2,5-dione;
1-[3-[4-(3-aminopropyl)-1-piperazinyl]propyl]-3-[[3-[4-(3-aminopropyl)-1-piperazinyl]propyl]amino]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;
3-(1H-indol-3-yl)-1-[3-(4-methyl-1-piperazinyl)propyl]-4-[[3-(4-methyl-1-piperazinyl)propyl]amino]-1H-pyrrole-2,5-dione;
3,3xe2x80x2-[iminobis(3,1-propanediylimino)]bis[4-(1H-indol-3-yl)-1H-pyrrole]-2,5-dione;
3,3xe2x80x2-[1,4-piperazinediylbis(3,1-propanediylimino)]bis[4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;
3-[(5-aminopentyl)amino]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;
3-[[5-(2-aminoethyl)amino]pentyl]amino]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;
3-[(2-aminoethyl)amino]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;
3-[(6-aminohexyl)amino]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;
3-[(7-aminoheptyl)amino]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;
3-[[2-[(2-aminoethyl)amino]ethyl]amino]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;
Benzenepropanamide, .alpha.-amino-N-[5-[[2,5-dihydro-4-(1H-indol-3-yl)-2,5-dioxo-1H-pyrrol-3-yl]amino]pentyl]-, (S)-;
Pentanoic acid, 4-amino-5-[[5-[[2,5-dihydro-4-(1H-indol-3-yl)-2,5-dioxo-1H-pyrrol-3-yl]amino]pentyl]amino]-5-oxo-, (S)-;
Pentanamide, 2-amino-5-[(aminoiminomethyl)amino]-N-[2-[[5-[[2,5-dihydro-4-(1H-indol-3-yl)-2,5-dioxo-1H-pyrrol-3-yl]amino]pentyl]amino]ethyl]-, (S)-;
Benzenepropanamide, .alpha.-amino-N-[2-[[5-[[2,5-dihydro-4-(1H-indol-3-yl)-2,5-dioxo-1H-pyrrol-3-yl]amino]pentyl]amino]ethyl]-, (S)-;
Butanamide, 4-[(aminoiminomethyl)amino]-N-[5-[[2,5-dihydro-4-(1H-indol-3-yl)-2,5-dioxo-1H-pyrrol-3-yl]amino]pentyl]-, (S)-;
3-phenyl-4-diethylamino)-pyrrole-2,5-dione;
3-phenyl-4-(benzylamino)-pyrrole-2,5-dione;
1-methyl-3-phenyl-4-(2-diethylaminoethylamino)-pyrrole-2,5-dione;
1-allyl-3-phenyl-4-(2-dimethylaminoethylamino)-pyrrole-2,5-dione; and;
1,3-diphenyl-4-piperidino-pyrrole-2,5-dione.
There is a further sub-group of compounds, falling wholly within formula (I), and being of formula (IB), wherein R, R1, R2 and R3 are as defined in relation to formula (I), with the proviso that formula (IB) does not include the following compounds, hereinafter referred to as List B:
3-(4-methylpiperazin-1-yl)-4-phenyl-pyrrole-2,5-dione;
3-(4-ethylpiperazin-1-yl)-4-phenyl-pyrrole-2,5-dione;
3-(4-chlorophenyl)-4-(4-methyl-piperazin-1-yl)-pyrrole-2,5-dione;
3-[4-(diphenylmethyl)-1-piperazinyl]-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;
3-phenyl-4-(4-methylpiperazino)-pyrrole-2,5-dione;
3-phenyl-4-(4-phenylpiperazino)-pyrrole-2,5-dione;
1-methyl-3-phenyl-4-(4-phenylpiperazino)-pyrrole-2,5-dione;
1-ethyl-3-phenyl-4-(4-chlorophenylpiperazino)-pyrrole-2,5-dione;
1-allyl-3-phenyl-4-(4-methylpiperazino)pyrrole-2,5-dione;
3-phenylamino-4-phenyl-1H-pyrrole-2,5-dione;
3-phenyl-4-piperidin-1-yl-pyrrole-2,5-dione;
3-(3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl)-4-morpholin-4-yl-pyrrole-2,5-dione;
3-indol-1-yl-4-(1-methyl-1H-indol-3-yl)-pyrrole-2,5-dione;
1-(1-methyl-2,5-dioxo-4-phenylamino-2,5-dihydro-1H-pyrrol-3-yl)pyridinium chloride;
1-1-(4-methyl-pentyl)-2,5-dioxo-4-phenylamino-2,5-dihydro-1H-pyrrol-3-yl)-pyridinium chloride;
1-(1-dodecyl-2,5-dioxo-4-phenylamino-2,5-dihydro-1H-pyrrol-3-yl)-pyridinium chloride;
3-[2,5-dihydro-4-(1H-imidazol-1-yl)-1-methyl-2,5-dioxo-1H-pyrrol-3-yl]-1H-indole-1-carboxylic acid, 1,1-dimethylethyl ester;
3-[2-benzo[b]thien-2-yl-3-[4-dimethylamino)-2,5-dihydro-2,5-dioxo-1H-pyrrol-3-yl]-1H-indol-1-yl]-carbamimidothioic acid, propyl ester;
3-(dimethylamino)-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;
3-(1H-indol-3-yl)-1-methyl-4-(phenylamino)-1H-pyrrole-2,5-dione;
3-(1H-indol-3-yl)-1-methyl-4-[[4-(trifluoromethyl)phenyl]amino]-1H-pyrrole-2,5-dione;
3-(1H-indol-3-yl)-1-methyl-4-(methylamino)-1H-pyrrole-2,5-dione;
3-(1H-imidazo[4,5-b]pyridin-1-yl)-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;
3-(6-chloro-9H-purin-9-yl)-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;
3-(6-amino-9H-purin-9-yl)-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;
3-(1H-indol-3-yl)-1-methyl-4-(1H-pyrrolo[2,3-b]pyridin-1-yl)-1H-pyrrole-2,5-dione;
3-(1H-indol-1-yl)-1-methyl-4-(1-piperidinyl)-1H-pyrrole-2,5-dione;
1-acetyl-3-[2,5-dihydro-1-methyl-2,5-dioxo-4-[[4-(trifluoromethyl)phenyl]amino]-1H-pyrrol-3-yl]-1H-indole:
3-(1H-benzimidazol-1-yl)-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;
3-(1H-benzotriazol-1-yl)-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;
3-(1H-imidazol-1-yl)-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;
3-(1H-indol-1-yl)-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;
3-(1H-indazol-1-yl)-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;
3-[3-[(dimethylamino)methyl]-1H-indol-1-yl]-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;
3-(1H-benzimidazol-1-yl)-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;
3-(1H-indol-1-yl-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione;
3-(3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl)-4-4-morpholinyl)-1H-pyrrole-2,5-dione;
3-amino-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;
3-amino-4-(5-methoxy-1H-indol-3-yl)-1H-pyrrole-2,5-dione;
1H-Indole-1-carboxylic acid, 3-(4-amino-2,5-dihydro-1-methyl-2,5-dioxo-1H-pyrrol-3-yl)-, 1,1-dimethylethyl ester;
3-(1H-indol-3-yl)-1-methyl-4-[(phenylmethyl)amino]-1H-pyrrole-2,5-dione;
Glycine, N-[2,5-dihydro-4-(1H-indol-3-yl)-1-methyl-2,5-dioxo-1H-pyrrol-3-yl]-, ethyl ester;
3-amino-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;
1-(4-methylphenyl)-3-[(4-methylphenyl)amino]-4-phenyl-1H-pyrrole-2,5-dione;
3-[[3-[(3-aminopropyl)amino]propyl]amino]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;
3-[[3-[4-(3-aminopropyl)-1-piperazinyl]propyl]amino]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;
3-(1H-indol-3-yl)-4-[[3-(4-methyl-1-piperazinyl)propyl]amino]-1H-pyrrole-2,5-dione;
1-[3-[(3-aminopropyl)amino]propyl]-3-[[3-[(3-aminopropyl)amino]propyl]amino]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;
1-[3-[4-(3-aminopropyl) 1-piperazinyl]propyl]-3-[[3-[4-(3-aminopropyl)-1-piperazinyl]propyl]amino]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;
3-(1H-indol-3-yl)-1-[3-(4-methyl-1-piperazinyl)propyl]-4-[[3-(4-methyl-1-piperazinyl)propyl]amino]-1H-pyrrole-2,5-dione;
3,3xe2x80x2-iminobis(3,1-propanediylimino)]bis[4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;
3,3xe2x80x2-[1,4-piperazinediylbis(3,1-propanediylimino)]bis[4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;
3-amino-4-(3,4-dimethoxyphenyl)-1H-pyrrole-2,5-dione;
3-[(5-aminopentyl)amino]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;
3-[[5-[(2-aminoethyl)amino]pentyl]amino]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;
3-[(2-aminoethyl)amino]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;
3-[(6-aminohexyl)amino]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;
3-[(7-aminoheptyl)amino]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;
3-[[2-[(2-aminoethyl)amino]ethyl]amino]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;
Benzenepropanamide, .alpha.-amino-N-[5-[[2,5-dihydro-4-(1H-indol-3-yl)-2,5-dioxo-1H-pyrrol-3-yl]amino]pentyl]-, (S)-;
Pentanoic acid. 4-amino-5-[[5-[[2,5-dihydro-4-(1H-indol-3-yl)-2,5-dioxo-1H-pyrrol-3-yl]amino]pentyl]amino]-5-oxo-, (S)-;
Pentanamide, 2-amino-5-[(aminoiminomethyl)amino]-N-[2-[[5-[[2,5-dihydro-4-(1H-indol-3-yl)-2,5-dioxo-1H-pyrrol-3-yl]amino]pentyl]amino]ethyl]-, (S)-;
Benzenepropanamide, .alpha.-amino-N-[2-[[5-[[2,5-dihydro-4-(1H-indol-3-yl)-2,5-dioxo-1H-pyrrol-3-yl]amino]pentyl]amino]ethyl]-, (S)-;
Butanamide, 4-[(aminoiminomethyl)amino]-N-[5-[[2,5-dihydro-4-(1H-indol-3-yl)-2,5-dioxo-1H-pyrrol-3-yl]amino]pentyl]-, (S)-;
3-(4-methylphenyl)-1-phenyl-4-(phenylamino)-1H-pyrrole-2,5-dione;
1,3-bis(4-methylphenyl)-4-((4-methylphenyl)amino]-1H-pyrrole-2,5-dione;
3-amino-1,4-diphenyl-1H-pyrrole-2,5-dione;
3-(4-methylphenyl)-4-(4-morpholinyl)-1-phenyl-1H-pyrrole-2,5-dione;
3-(4-methylphenyl)-1-phenyl-4-((phenylmethyl)amino]-1H-pyrrole-2,5-dione;
3-amino-4-(4-methylphenyl)-1-phenyl-1H-pyrrole-2,5-dione;
3-(3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl)-4-(4-morpholinyl)-1H-pyrrole-2,5-dione;
3-(4-nitrophenyl)-1-phenyl-4-phenylamino-1H-pyrrole-2,5-dione;
3-amino-1-methyl-4-p-tolyl-1H-pyrrole-2,5-dione;
3-(2-diethylamino-ethylamino)-4-phenyl-pyrrole-2,5-dione;
3-[butyl-(2-diethylamino-ethyl)-amino]-4-phenyl-pyrrole-2,5-dione;
3-[benzyl-(2-dimethylamino-ethyl)-amino]-4-phenyl-pyrrole-2,5-dione;
3-[benzyl-(2-dimethylamino-ethyl)amino]-1-methyl-4-phenyl-pyrrole-2,5-dione;
3-[benzyl-(2-dimethylamino-ethyl)-amino-4-(4-chloro-phenyl)-pyrrole-2,5-dione;
3-[benzyl-(2-diethylamino-ethyl)-amino]-4-phenyl-pyrrole-2,5-dione;
3-[benzyl-(2-dimethylamino-ethyl)-amino](3-methoxy-phenyl)-pyrrole-2,5-dione;
3-(4-chloro-phenyl)-4-[2-(4-methyl-piperazin-1-yl)-ethylamino]-pyrrole-2,5-dione;
3-[2-(4-methyl-piperazin-1-yl)-ethylamino]-4-phenyl-pyrrole-2,5-dione;
3-phenyl-4-(diethylamino)pyrrole-2,5-dione;
3-phenyl-4-(benzylamino)-pyrrole-2,5-dione;
1-methyl-3-phenyl-4-(2-diethylaminoethylamino)-pyrrole-2,5-dione;
1-allyl-3-phenyl-4-(2-dimethylaminoethylatnino)-pyrrole-2,5-dione; and;
1,3-diphenyl-4-piperidino-pyrrole-2,5-dione.
It is considered that the compounds of formula (IB) are novel. Accordingly, the present invention also provides a compound of the above defined formula (IB) or a derivative thereof.
There is a subgroup of compounds falling wholly within formula (I) of formula (IC): 
wherein:
R and R1 are as defined in relation to formula (I);
R10 represents hydrogen or one or more substituents, suitably up to three, selected from the list consisting of: alkoxycarbonyl, alkoxyalkyl, perfluoroalkyl, perfluoroalkylSxe2x80x94, perfluoroalkylOxe2x80x94, phenyl(di-C1-6alkoxy)Cxe2x80x94, benzoyl, C1-6alkylSO2xe2x80x94, xe2x80x94[(CHxe2x95x90CH)2]xe2x80x94, phenyl, nitro, xe2x80x94OCH2Oxe2x80x94, benzyloxy, phenoxy, halo, hydroxy, alkyl, alkoxy, amino, mono- or di-alkyl amino or thioalkyl;
R11 represents hydrogen or one or more substituents, suitably up to three, selected from the list consisting of: substituted or unsubstituted C1-6alkyl, phenyl, benzyl, substituted or unsubstituted C1-6alkylSxe2x80x94, halo, hydroxy, substituted or unsubstituted C1-6alkoxy, substituted or unsubstituted phenoxy, indolyl, naphthyl, carboxy, C1-6alkoxycarbonyl, benzyloxy, phenoxy, pentafluorophenoxy, nitro, substituted or unsubstituted carbamoyl, substituted or unsubstituted C1-6alkylcarbonyl, benzoyl, cyano, perfluoroC1-6alkylSO2xe2x80x94, C1-6alkylNHSO2xe2x80x94, oxazolyl, substituted or unsubstituted phenylSxe2x80x94, C1-6alkylpiperazinyl-, C1-6alkylcarbonylpiperazinyl-, 1,2,3-thiadiazolyl, pyrimidin-2-yloxy, N-[pyriidin-2-yl]-N-methylamino, phenylamino, C1-6alkylsulphonylamino, N-morpholinylcarbonyl, cyclohexyl, adamantyl, trityl, substituted or unsubstituted C1-6alkenyl, perfluoroC1-6alkyl, perfluoroC1-6alkoxy, perfluoroC1-6akylSxe2x80x94, aminosulphonyl, morpholino, (diC1-6alkyl)amino, C1-6alkylCONHxe2x80x94, (diC1-6alkoxy)phenyl(CH2)nNHC(O)CH(phenyl)Sxe2x80x94 where n is 1 to 6, and C1-6alkylCON(C1-6alkyl)xe2x80x94, thiazolidinedionylC1-6alkyl, phenylCH(OH)xe2x80x94, substituted or unsubstituted piperazinylC1-6alkoxy, substituted or unsubstituted benzoylamino; or xe2x80x94(CH2)xxe2x80x94, xe2x80x94SCHxe2x95x90Nxe2x80x94, xe2x80x94SC(C1-6alkyl)xe2x95x90Nxe2x80x94, xe2x80x94OCF2Oxe2x80x94, xe2x80x94[CHxe2x95x90CHC(O)O]xe2x80x94, xe2x80x94[Nxe2x95x90CHxe2x80x94CHxe2x95x90CH]xe2x80x94, xe2x80x94CHxe2x95x90Nxe2x80x94NHxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94NHxe2x80x94, xe2x80x94OC(NHC1-6alkyl)xe2x95x90Nxe2x80x94, xe2x80x94OC(O)NHxe2x80x94, xe2x80x94C(O)NMeC(O)xe2x80x94, xe2x80x94C(O)NHC(O)xe2x80x94, xe2x80x94CH2)xC(O)xe2x80x94, xe2x80x94Nxe2x95x90Nxe2x80x94NHxe2x80x94, xe2x80x94Nxe2x95x90C(C1-6alkyl)Oxe2x80x94, xe2x80x94O(CH2)xOxe2x80x94, xe2x80x94(CH2)xSO2(CH2)yxe2x80x94, and xe2x80x94N(C1-6alkylcarbonyl)(CH2)xxe2x80x94, where x and y are independently 1 to 4.
There is a subgroup of compounds within formula (IC) of formula (ICxe2x80x2) wherein R, R1, R10 and R11 are as defined in relation to formula (IC) with the proviso that formula (ICxe2x80x2) does not include:
3-phenylamino-4-phenyl-1H-pyrrole-2,5-dione;
1-(4-methylphenyl)-3-[(4-methylphenyl)amino]-4-phenyl-1H-pyrrole-2,5-dione;
3-(4-methylphenyl)-1-phenyly-4-phenylamino)-1H-pyrrole-2,5-dione;
1,3-bis(4-methylphenyl)-4-[(4-methylphenyl)amino]-1H-yrrole-2,5-dione, or,
3-(4-nitrophenyl)-1-phenylphenylamino-1H-pyrrole-2,5-dione.
Suitably, R is hydrogen.
Suitably, R1 is hydrogen.
Suitably, R10 represents hydrogen or one or more substituents selected from the list consisting of: halo, hydroxy, alkyl, alkylthio, alkoxy, amino or methylenedioxy. especially one or more halo and alkyl groups.
Favourably, R10 represents hydrogen or the substituents selected from the list consisting of: 2-Br, 2-Cl, 2-F, 2-OMe, 3-Cl, 3-F, 3-Me, 3-NH2, 3-OMe, 4-Br, 4-Cl, 4-I, 4-Me, 4-OH, 4-OMe, 4-SMe, 2,3-di-F, 2,5-di-F, 2,6-di-F, 3,4-di-F, 3,5-di-F, 2,3,5-tri-F, 2,4-di-Cl, 2,4-di-OMe, 3,4-(OCH2O) and 3,5-di-Me.
More favourably, R10 represents the substituents selected from the list consisting of: 2-Br, 2-Cl, 2-F, 2-OMe, 3-Cl, 3-F, 3-Me, 4-Br, 4-Cl, 4-I, 2,3-di-F, 2,5-di-F, 2,6-di-F, 3,4-di-F, 3,5-di-F, 2,3,5-tri-F, 2,4-di-Cl and 3,5-di-Me.
Preferably, R10 represents the substituents selected from the list consisting of: 2-F, 2-OMe, 3-F, 4-Cl and 2,3-di-F.
Suitably, R11 represents hydrogen or one or more substituents selected from the list consisting of: 2-F, 2-Me, 3-Br, 3-Cl, 3-F, 3-I, 3-OH, 3-OMe, 3-OPh, 3-SMe, 3-CO2H, 3-CH2CO2H, 3-CH2CO2Me, 3-CH2CONH2, 3-CH2CONHMe, 3-CH2OH, 4-Cl, 4-F, 4-Me, 4-NHCOMe, 4-NHPh, 4-NHSO2Me, 4-NMe2, 4-OMe, 4-COPh, 4-SMe, 4-CH2CN, 4-SO2NH2, 4-(CH2)2OH, 4-CH(OH)Ph, 4-CH2SO2NHMe, 4-CH2CO2H, 4-(CH2)2CO2H, 4-(CH2)2CO2Me, 4-(CH2)2CONH2, 4-CH2)3CO2H, 4-(CH2)3CONH2, 4-CHxe2x95x90CHCO2H, 4-CHxe2x95x90CHCONH2, 4-OCH2CO2H, 4-SCH2CO2H, 4-S-[2-CO2H-Ph], 4-S-(3-CO2H-Ph], 4-CH2(1,3-thiazolidin-2,4-dion-5-yl), 2,3-di-F, 2,4-di-F, 3,4-di-F 3,5-di-F, 3-Cl-4-Br, 3-Cl-4-Me, 3-Br-4-Me, 3-Cl-4-OH, 3-Cl-4-OMe, 3,5-di-Me, 3,5-di-OMe, 3,4-OC(O)NHxe2x80x94, 3,4-OCF2Oxe2x80x94, 3,5-di-Br-4-OH, 3,5-di-Cl-4-Me, 3,5-di-Cl-4-OH, 3-CO2H-4-[S-(2-CO2H)-Ph], 3-CO2H-4-[S-(2-CONHMe)-Ph], 3-CO2H-4-Cl, 3-F-4-Me, 3-F-4-OMe, -3,4-[(CHxe2x95x90Nxe2x80x94NH)]xe2x80x94, -3,4-[(Nxe2x95x90Nxe2x80x94NH)]xe2x80x94, -3,4-[(NHxe2x80x94Nxe2x95x90CH)]xe2x80x94, -3,4-[(CH2)3]xe2x80x94, -3,4-[(O(CH2)3O)]xe2x80x94, -3,4-[Oxe2x80x94C(NHMe)xe2x95x90N]xe2x80x94, -3,4-[OCH2O]xe2x80x94, -3,4-[Sxe2x80x94C(NHMe)xe2x95x90N]xe2x80x94 and -3,4-[Sxe2x80x94CHxe2x95x90N]xe2x80x94,
Favourably, R11 represents hydrogen or the substituents selected from the list consisting of: 2-F, 2-Me, 3-Cl, 3-F, 3-I, 3-OMe, 3-OPh, 3-SMe, 3-CH2CO2H, 3-CH2CO2Me, 3-CH2CONH2, 3-CH2CONHMe, 3-CH2OH, 4-Cl, 4-F, 4-NHCOMe, 4-NHPh, 4-NHSO2Me, 4-NMe2, 4-OMe, 4-COPh, 4-SMe, 4-CH2CN, 4-SO2NH2, 4-(CH2)2OH, 4-CH(OH)Ph, 4-CH2SO2NHMe, 4-CH2CO2H, 4-(CH2)2CO2H, 4-(CH2)2CO2Me, 4-(CH2)2CONH2, 4-(CH2)3CO2H, 4-(CH2)3CONH2, 4-CHxe2x95x90CHCONH2, 4-OCH2CO2H, 4-SCH2CO2H, 4-S-[2-CO2H-Ph], 4-S-[3-CO2H-Ph], 4-CH2(1,3-thiazolidin-2,4-dion-5-yl 2,3-di-F, 2,4-di-F, 3,4-di-F, 3,5-di-F, 3-Cl-4-Br, 3-Cl-4-Me, 3-Br-4-Me, 3-Cl-4-OH, 3-Cl-4-OMe, 3,5-di-Me, 3,5-di-OMe, 3,4-[OC(O)NH], 3,4-[OCF2O] 3,5-di-Cl-4-Me, 3-CO2)H-4-[S-(2-CONHMe)Ph], 3-F-4-Me, 3-F-4-OMe, 3,4-[(CHxe2x95x90Nxe2x80x94NH)], 3,4-[(Nxe2x95x90Nxe2x80x94NH)], 3,4-[(NHxe2x80x94Nxe2x95x90CH)], 3,4-[(CH2)3], 3,4-[O(CH2)3O], 3,4-[Oxe2x80x94C(NHMe)xe2x95x90N], 3,4-[OCH2O], 3,4-[Sxe2x80x94C(NHMe)xe2x95x90N] and 3,4-[Sxe2x80x94CHxe2x95x90N].
More favourably, R11 represents the substituents selected from the list consisting of: 3-Cl, 3-Br, 4-OMe, 3,5-di-F, 4-CH2SO2NHMe, 4-CH2)3CO2H and 4-S-[3-CO2H-Ph].
A particular compound of formula (IC) is that wherein R and R1 each represent hydrogen and R10 and R11 each have the following respective values:
It is considered that the compounds of formula (ICxe2x80x2) are novel. Accordingly, the present invention also provides a compound of the above defined formula (ICxe2x80x2) or a derivative thereof.
There is a subgroup of compounds falling wholly within formula (I) being of formula (ID): 
wherein R and R1 are as defined in relation to formula (I);
R2xe2x80x2 is phenyl, substituted phenyl or indolyl;
R3xe2x80x2 is hydrogen, alkyl, cycloalkyl, phenyl, substituted phenyl, C1-6alkylphenyl wherein the phenyl group is optionally substituted, alkoxyalkyl, substituted or unsubstinuted heterocyclyl.
In one aspect, there is provided a compound of formula (I) as hereinbefore defined which excludes compounds of formula (ID).
There is a subgroup of compounds within formula (ID) of formula (IDxe2x80x2) wherein R, R1, R2xe2x80x2 and R3xe2x80x2 are as defined in relation to formula (ID) with the proviso that formula (IDxe2x80x2) does not include the following compounds, hereinafter referred to as List Dxe2x80x2:
3-[2-benzo[b]thien-2-yl-3-[4-dimethylamino)-2,5-dihydro-2,5-dioxo-1H-pyrrol-3-yl]-1H-indol-1-yl]-carbamimidothioic acid, propyl ester;
3-(dimethylamino)-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;
3-(1H-indol-3-yl)-1-methyl-4-(phenylamino)-1H-pyrrole-2,5-dione;
3-(1H-indol-3-yl)-1-methyl-4-[[4-trifluoromethyl)phenyl]amino]-1H-pyrrole-2,5-dione;
3-(1H-indol-3-yl)-1-methyl-4-methylamino)-1H-pyrrole-2,5-dione;
3-(6-chloro-9H-purin-9-yl)-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;
3-(6-amino-9H-purin-9-yl)-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;
1-acetyl-3-[2,5-dihydro-1-methyl-2,5-dioxo-4-[[4-(trifluoromethyl)phenyl]amino]-1H-pyrrol-3-yl]-1H-indole;
3-amino-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;
3-amino-4-(5-methoxy-1H-indol-3-yl)-1H-pyrrole-2,5-dione;
1H-Indole-1-carboxylic acid, 3-(4-amino-2,5-dihydro-1-methyl-2,5-dioxo-1H-pyrrol-3-yl)-, 1,1-dimethylethyl ester;
3-(1H-indol-3-yl)-1-methyl-4-[(phenylmethyl)amino]-1H-pyrrole-2,5-dione;
Glycine, N-[2,5-dihydro-4-(1H-indol-3-yl)-1-methyl-2,5-dioxo-1H-pyrrol-3-yl]-, ethyl ester;
3-amino-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;
3-[[3-[(3-aminopropyl)amino]propyl]amino]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;
3-[[3-[4-(3-aminopropyl)-1-piperazinyl]propyl]amino]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;
3-(1H-indol-3-yl)-4-[[3-(4-methyl-1-piperazinyl)propyl]amino]-1H-pyrrole-2,5-dione;
1-[3-[(3-aminopropyl)amino]propyl]-3-[[3-[(3-aminopropyl)amino]propyl]amino]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;
1-[3-[4-(3-aminopropyl)-1-piperazinyl]propyl]-3-[[3-[4-(3-aminopropyl)-1-piperazinyl]propyl]amino]-4-1H-indol-3-yl)-1H-pyrrole-2,5-dione;
3-(1H-indol-3-yl)-1-[3-(4-methyl-1-piperazinyl)propyl]-4-[[3-(4-methyl-1-piperazinyl)propyl]amino]-1H-pyrrole-2,5-dione;
3,3xe2x80x2-[iminobis(3,1-propanediylimino)]bis[4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;
3,3xe2x80x2-[1,4-piperazinediylbis(3,1-propanediylimino)]bis[4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;
3-amino-4-(3,4-dimethoxyphenyl)-1H-pyrrole-2,5-dione;
3-[(5-aminopentyl)amino-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;
3-[[5-[(2-aminoethyl)amino]pentyl]amino]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;
3-[(2-aminoethyl)amino]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;
3-[(6-aminohexyl)amino]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;
3-[(7-aminoheptyl)amino]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;
3-[[2-[(2-aminoethyl)amino]ethyl]amino]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione;
Benzenepropanamide, .alpha.-amino-N-[5-[[2,5-dihydro-4-(1H-indol-3-yl)-2,5-dioxo-1H-pyrrol-3-yl]amino]pentyl]-, (S)-;
Pentanoic acid, 4-amino-5-[[5-[[2,5-dihydro-4-(1H-indol-3-yl)-2,5-dioxo-1H-pyrrol-3-yl]amino]pentyl]amino]-5-oxo-, (S)-;
Pentanamide, 2-amino-5-[(aminoiminomethyl)amino]-N-[2-[[5-[(2,5-dihydro-4-(1H-indol-3-yl)-2,5-dioxo-1H-pyrrol-3-yl]amino]pentyl]amino]ethyl]-, (S)-;
Benzenepropanamide, .alpha.-amino-N-[2-[[5-[[2,5-dihydro-4-(1H-indol-3-yl)-2,5-dioxo-1H-pyrrol-3-yl]amino]pentyl]amino]ethyl]-, (S)-;
Butanamide, 4-[(aminoiminomethyl)amino]-N-[5-[[2,5-dihydro-4-(1H-indol-3-yl)-2,5-dioxo-1H-pyrrol-3-yl]amino]pentyl]-, (S)-;
3-amino-1,4-diphenyl-1H-pyrrole-2,5-dione;
3-(4-methylphenyl)-1-phenyl-4-[(phenylmethyl)amino]-1H-pyrrole-2,5-dione;
3-amino-4-(4-methylphenyl)-1-phenyl-1H-pyrrole-2,5-dione;
3-amino-1-methyl-4-p-tolyl-1H-pyrrole-2,5-dione;
3-(2-diethylamino-ethylamino)-4-phenyl-pyrrole-2,5-dione;
3-[butyl-(2-diethylamino-ethyl)-amino]-4-phenyl-pyrrole-2,5-dione;
3-[benzyl-(2-dimethylamino-ethyl)-amino]-4-phenyl-pyrrole-2,5-dione;
3-[benzyl-(2-dimethylamino-ethyl)-amino]-1-methyl-4-phenyl-pyrrole-2,5-dione;
3-[benzyl-(2-dimethylamino-ethyl)-amino]-4-(4-chloro-phenyl)-pyrrole-2,5-dione;
3-[benzyl-(2-diethylamino-ethyl)-amino]-4-phenyl-pyrrole-2,5-dione;
3-[benzyl-(2-dimethylamino-ethyl)-amino]-4-(3-methoxy-phenyl)-pyrrole-2,5-dione;
3-(4-chloro-phenyl)-4-[2-(4-methyl-piperazin-1-yl)-ethylamino]-pyrrole-2,5-dione;
3-[2-(4-methyl-piperazin-1-yl)-ethylamino]-4-phenyl-pyrrole-2,5-dione;
3-phenyl-4-(diethylamino)-pyrrole-2,5-dione;
3-phenyl-4-(benzylamino)-pyrrole-2,5-dione;
1-methyl-3-phenyl-4-(2-diethylaminoethylamino)-pyrrole-2,5-dione, and;
1-allyl-3-phenyl-4-(2-dimethylaminoethylainino)-pyrrole-2,5-dione.
Suitably R2xe2x80x2 is indolyl, phenyl or phenyl substituted with one or more, suitably up to three, substituents selected from the list consisting of: halo, haloalkyl, alkoxy, nitro, alkyl and alkoxy.
Examples of R2xe2x80x2 include phenyl, indol-3-yl, 2-methoxyphenyl, 3-fluorophenyl, 3-nitrophenyl, 4-chlorophenyl, 4-iodophenyl, 4-(trifluoromethyl)phenyl and 2,3-difluorophenyl.
Suitably R3xe2x80x2 represents hydrogen, C1-6alkyl, cyclohexyl, phenyl, fluorenyl, C1-2alkylphenyl, C1-6alkoxyC1-2alkyl or a substituted or unsubstituted single or a single or fused ring heterocyclyl group having 5 or 6 ring atoms and up to 3 hetero atoms in each ring, such as oxazolyl, benzofuranyl, dibenzofuranyl, pyridinyl, quinolinyl, pyrimidinyl.
Examples of R3xe2x80x2 include hydrogen, ethyl, cyclohexyl, phenyl, fluoren-2-yl, benzyl, phenyl(CH2)2xe2x80x94, MeO(CH2)2xe2x80x94, 4-methyloxazol-2-yl, 2-acetylbenzofuran-5-yl, dibenzofuran-2-yl, dibenzofuran-3-yl, 2-methylpyridin-3-yl, 2,6-dimethylpyridin-3-yl, 2-chloropyridin-5-yl, quinolin-3-yl, pyrimidin-2-yl.
It is considered that the compounds of formula (IDxe2x80x2) are novel. Accordingly, the present invention also provides a compound of the above defined formula (IDxe2x80x2) or a derivative thereof.
There is a subgroup of compounds falling wholly within formula (I) being of formula (IE): 
wherein R is as defined in relation to formula (I);
R10xe2x80x2 represents hydrogen or one or more, suitably up to three, substituents selected from the list consisting of: alkoxy, halo, and nitro; Pxe2x80x2xe2x80x94Qxe2x80x2 represents xe2x80x94(CH2)aO(CH2)bxe2x80x94, xe2x80x94(CH2)aS(CH2)bxe2x80x94, xe2x80x94(CH2)cxe2x80x94, xe2x80x94(CH2)dCH(G)(CH2)exe2x80x94, xe2x80x94(CH2)aN(ZZ)(CH2)bxe2x80x94, where a, b, d, and e are independently 1 to 4, c is 1 to 6, ZZ is hydrogen, alkyl, aryl, or alkylcarbonyl, and G is alkyl, amido, hydroxyalkyl, aralkyl, or hydroxy.
There is a subgroup ot compounds within formula (IE) of formula (IExe2x80x2) wvherein R, R10xe2x80x2, and Pxe2x80x2xe2x80x94Qxe2x80x2 are as defined in relation to formula (IE) with the proviso that formula (IExe2x80x2) does not include:
3-phenyl-4-piperidin-1-yl-pyrrole-2,5-dione;
3-(4-methylpiperazin-1-yl)-4-phenyl-pyrrole-2,5-dione;
3-(4-ethylpiperazin-1-yl)-4-phenyl-pyrrole-2,5-dione;
3-(4-chlorophenyl)-4-(4-methyl-piperazin-1-yl)-pyrrole-2,5-dione;
3-(4-methylphenyl)-4-(4-morpholinyl)-1-phenyl-1H-pyrrole-2,5-dione;
3-phenyl-4-(4-methylpiperazino)-pyrrole-2,5-dione;
3-phenyl-4-(4-phenylpiperazino)-pyrrole-2,5-dione;
1-methyl-3-phenyl-4-(4-phenylpiperazino)pyrrole-2,5-dione;
1-ethyl-3-phenyl-4-(4-chlorophenylpiperazino)-pyrrole-2,5-dione;
1-allyl-3-phenyl-4-(4-methylpiperazino)-pyrrole-2,5-dione, and;
1,3-diphenyl-4-piperidino-pyrrole-2,5-dione.
Suitably, R10xe2x80x2 is methoxy, chloro, or nitro.
Examples of R10xe2x80x2 include 4-methoxy, 4-chloro, 2,4-dichloro, and 3-nitro.
Examples of xe2x80x94Pxe2x80x2xe2x80x94Qxe2x80x2xe2x80x94 include xe2x80x94(CH2)4xe2x80x94, xe2x80x94(CH2)2O(CH2)2xe2x80x94, xe2x80x94(CH2)3CH(Me)CH2xe2x80x94, xe2x80x94(CH2)3CH(CONH2)CH2xe2x80x94, xe2x80x94(CH2)3CH(CH2OH)CH2xe2x80x94, xe2x80x94(CH2)2CH(CH2Ph)(CH2)2xe2x80x94, xe2x80x94(CH)2CH(OH)(CH2)2xe2x80x94, xe2x80x94(CH2)5xe2x80x94, and xe2x80x94(CH2)S(CH2)2xe2x80x94.
It is considered that the compounds of formula (IExe2x80x2 are novel. Accordingly, the present invention also provides a compound of the above defined formula (IExe2x80x2) or a derivative thereof.
There is a subgroup of compounds falling wholly within formula (I) being of formula (IF): 
wherein R is as defined in relation to formula (I);
R10xe2x80x3 is one or more, suitably up to three, substituents selected from the list consisting of perfluoroalkyl, halo, nitro, alkoxy, arylcarbonyl, alkyl;
Z is a bond or an alkylene chain;
xe2x80x94Xxe2x80x94Yxe2x80x94 is xe2x80x94CHxe2x95x90N, xe2x80x94(CH2)txe2x80x94, xe2x80x94(CH2)uCH(U)xe2x80x94, xe2x80x94(U)CH(CH2)uxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94(CH2)vC(alkyl)2xe2x80x94, xe2x80x94C(O)C(alkyl)2xe2x80x94, xe2x80x94C(O)Oxe2x80x94, where t, u, and v are independently 1 to 4, and U is alkyl, carboxy, alkoxycarbonyl, hydroxyalkyl, and amido;
R12axe2x80x2, R12bxe2x80x2, and R12cxe2x80x2 are each independently hydrogen, nitro, alkoxy, 4-ethylpiperazin-1-yl, 4-BOC-piperazin-1-yl, 4-methyl-piperazin-1-yl, 4-methyl-piperazin-1-yl, halo, alkyl, piperazin-1-yl, perfluoroalkyl, and alkylsulphonylamino.
Suitably, Z is a bond or a C1-2alkylene chain.
Examples of Z include a bond, methylene or ethylene.
Examples of xe2x80x94Xxe2x80x94Yxe2x80x94 are xe2x80x94CHxe2x95x90Nxe2x80x94, xe2x80x94(CH2)2xe2x80x94, xe2x80x94CH(Me)CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH(CO2H)CH2xe2x80x94, xe2x80x94CH(CO2Me)CH2xe2x80x94, xe2x80x94(CH2)3xe2x80x94, xe2x80x94CH(CH2OH)CH2xe2x80x94, xe2x80x94CH2CH(CH2OH)xe2x80x94, xe2x80x94CH2CH(Me)xe2x80x94, xe2x80x94CH2C(Me)2xe2x80x94, xe2x80x94CH(CONH2)CH2xe2x80x94, xe2x80x94C(O)C(MeCxe2x80x94, and xe2x80x94C(O)Oxe2x80x94.
Examples of R12axe2x80x2, R12bxe2x80x2, and R12cxe2x80x2 include hydrogen, nitro, fluoro, methoxy, 4-ethylpiperazin-1-yl, 4-BOC-piperazin-1-yl, 4-methyl-piperazin-1-yl, 4-methyl-piperazin-1-yl, chloro, bromo, trifluoromethyl, and methanesulphonylamino.
Preferably, Z is a bond.
Preferably, xe2x80x94Xxe2x80x94Yxe2x80x94 is xe2x80x94(CH2)2xe2x80x94 or xe2x80x94CH(CH2OH)CH2xe2x80x94, xe2x80x94CH(Me)CH2xe2x80x94, xe2x80x94CH2CH(Me)xe2x80x94, or xe2x80x94CH2C(Me)2xe2x80x94.
Preferably, R12bxe2x80x2 is fluorine.
Preferably, R12axe2x80x2 is fluorine.
Most preferably, R10xe2x80x3 is 2-Br, 2-Cl, 2-F, 2OMe, 3-Cl, 3-F, 3-Me, 4Br, 4-Cl, 4-I, 2,3-di-F, 2,5-di-F, 2,6-di-F, 3,4-di-F, 3,5-di-F, 2,3,5-tri-F, 2,4-di-Cl, 3,5-di-Me;
Z is a bond:
xe2x80x94Xxe2x80x94Yxe2x80x94 is xe2x80x94(CH2)2xe2x80x94 or xe2x80x94CH(CH2OH)CH2xe2x80x94, xe2x80x94CH(Me)CH2xe2x80x94, xe2x80x94CH2CH(Me)xe2x80x94, or xe2x80x94CH2C(Me)2xe2x80x94,
R12bxe2x80x2 is fluorine; and
R12axe2x80x2 is fluorine.
It is considered that the compounds of formula (IF) are novel. Accordingly, the present invention also provides a compound of the above defined formula (IF) or a derivative thereof. There isa subgroup of compounds falling wholly within formula (I) being of formula (IG): 
wherein R and R1 are as defined in relation to formula (I);
A is N(alkyl), oxygen, or sulphur.
Examples of A are N(methyl), oxygen, and sulphur.
Preferably, A is sulphur.
R11xe2x80x3 is one or more, suitably up to three, substituents selected from the group consisting of hydrogen, halo, alkyl, alkylthio, xe2x80x94Sxe2x80x94CHxe2x95x90Nxe2x80x94, phenoxy, xe2x80x94(CH2)wxe2x80x94, hydroxy, carboxy, xe2x80x94O(CH)xOxe2x80x94, hydroxyalkyl, and alkylaminosulphonylalkyl, where w and x are independently 1 to 4.
Examples of R11xe2x80x3 are hydrogen, bromo, methyl, methylthio, chloro, xe2x80x94Sxe2x80x94CHxe2x95x90Nxe2x80x94, phenoxy, xe2x80x94(CH2)3xe2x80x94, hydroxy, carboxy, xe2x80x94O(CH2)Oxe2x80x94, fluoro, hydroxymethyl, and MeNHSO2CH2xe2x80x94.
Preferably, R11xe2x80x3 is 3-Br, 4-Me, 4-SMe, 3-Br-4-Me, 3-Cl, 3,4-[Sxe2x80x94CHxe2x95x90N]xe2x80x94, 3-OPh, 3,4-[(CH2)3 ]xe2x80x94, 3-SMe, hydrogen, 3,5-diBr-4-OH, 3,5-diCl-4-OH, 3-CO2H-4-Cl, 3,4-[-OCH2O]xe2x80x94, 3-Cl-4-OH, 3,5-diF, 3-CH2OH, 3-OH, or 4-CH2SO2NHMe.
R13xe2x80x2 is one or more, suitably up to two, substituents selected from the group consisting of xe2x80x94CHxe2x95x90CH)2xe2x80x94 and hydrogen.
Examples of R13xe2x80x2 include 4,5-[(CHxe2x95x90CH)2]xe2x80x94 and hydrogen.
Preferably, R13xe2x80x2 is hydrogen.
It is considered that the compounds of formula (IG) are novel. Accordingly, the present invention also provides a compound of the above defined formula (IG) or a derivative thereof.
There is a subgroup of compounds falling wholly within formula (I) being of formula (IH): 
wherein R and R1 are as defined in relation to formula (I);
R11xe2x80x2xe2x80x3 is xe2x80x94[(CH2)aa]xe2x80x94, where aa is 1 to 4;
R14xe2x80x2 is hydrogen;
R15xe2x80x2 is alkyl, unsubstituted or substituted phenylamino, unsubstituted or substituted phenylalkylamino, cyclohexylamino, alkenylamino, phenyl, benzyl, styryl, or alkylamino.
Examples of R11xe2x80x2xe2x80x3 include 3,4-[(CH2)3].
Suitably, R15xe2x80x2 is C1-6alkyl, (halophenyl)amino, phenylalkylamino. cyclohexylamino, propenylaminio, phenyl, benzyl, styryl, propyl, ethylamino, or (methoxyphenyl)amino.
Examples of R15xe2x80x2 include methyl, (3-fluorophenyl)amino, phenylethylamino, cyclohexylamino, propenylamino, phenyl, benzyl, trans-styryl, n-propyl, ethylamino, and (3-methoxyphenyl)amino.
It is considered that the compounds of formula (IH) are novel. Accordingly, the present invention also provides a compound of the above defined formula (IH) or a derivative thereof.
There is a subgroup of compounds falling wholly within formula (I) being of formula (IJ): 
wherein R and R1 are as defuned in relation to formula (I);
R10xe2x80x2xe2x80x3 represents one or more, suitably up to three, substituents independently selected from alkoxy or halo;
R16xe2x80x2 represents one or more, suitably up to three, substituents independently selected from hydrogen, carboxy, alkoxycarbonyl, or alkylaminocarbonyl;
R17xe2x80x2 represents one or more, suitably up to three, substituents independently selected from carboxy, alkoxycarbonyl, halo, alkylaminocarbonyl, nitro, or hydrogen;
W is sulphur, oxygen, or substituted or unsubstituted NH.
Suitably, W is sulphur or oxygen. Favourably, W is sulphur.
Suitably, R10xe2x80x2xe2x80x3 is C1-6alkoxy, chloro, or fluoro.
Examples of R10xe2x80x2xe2x80x3 are methoxy, 4-chloro, 2-chloro, and 2,3-difluoro.
Favourably, R10xe2x80x2xe2x80x3 is 2,3-difluoro.
Suitably, R16xe2x80x2 is hydrogen, carboxy, C1-6alkoxycarbonyl, or C1-6alkylaminocarbonyl.
Examples of R16xe2x80x2 arc carboxy, hydrogen, ethoxycarbonyl, methoxycarbonyl, and methylaminocarbonyl.
Favourably, R16xe2x80x2 is hydrogen
Suitably, R17xe2x80x2 is carboxy, C1-6alkoxycarbonyl, halo, C1-6alkylaminocarbonyl, nitro, or hydrogen;
Examples of R17xe2x80x2 are 2-carboxy, 3-carboxy, 4-carboxy, 4-chloro, 2-methylaminocarbonyl, 4-nitro, hydrogen, and 2-ethoxycarbonyl.
Favourably, R17xe2x80x2 is 3-carboxy.
It is considered that the compounds of formula (IJ) are novel. Accordingly, the present invention also provides a compound of the above defined formula (II) or a derivative thereof.
There is a subgroup of compounds falling wholly within formula (I) being of formula (IK): 
wherein R and R1 are as defined in relation to formula (I);
R11xe2x80x3xe2x80x3 represents one or more, suitably up to three, substituents independently selected from halo and hydroxy;
R18xe2x80x2 represents one or more, suitably up to three, substituents independently selected from hydrogen, alkyl, and xe2x80x94CHxe2x95x90CH)2xe2x80x94;
A is sulphur.
Suitably, R11xe2x80x3xe2x80x3 is chloro or hydroxy.
Examples of R11 xe2x80x3xe2x80x3 are 3-chloro and 3,5-chloro-4-hydroxy.
Suitably, R18xe2x80x2 is hydrogen, C1-6alkyl, or xe2x80x94(CHxe2x95x90CH)2xe2x80x94,
Examples of R18xe2x80x2 include hydrogen, methyl, and 3-methyl-4,5-[(CHxe2x95x90CH)2]xe2x80x94,
It is considered that the compounds of formula (IK) are novel. Accordingly, the present invention also provides a compound of the above defined formula (IK) or a derivative thereof.
There is a subgroup of compounds falling wholly within formula (I) being of formula (IL): 
wherein R is as defined in relation to formula (I);
R2xe2x80x2xe2x80x3 is unsubstituted or substituted heterocyclyl or unsubstituted or substituted aryl;
R19xe2x80x2 is unsubstituted or substituted heterocyclyl, or a quaternised salt thereof.
There is a subgroup of compounds within formula (IL) of formula (ILxe2x80x2) wherein R, R2xe2x80x2xe2x80x3, and R19xe2x80x2 are as defined in relation to formula (IL) with the proviso that (ILxe2x80x2) does not include the following compounds, hereinafter referred to as List Lxe2x80x2:
3-indol-1-yl-4-(1-methyl-1H-indol-3-yl)-pyrrole-2,5-dione;
1-(1-methyl-2,5-dioxo-4-phenylamino-2,5-dihydro-1H-pyrrol-3-yl)-pyridinium chloride;
1-1-(4-methyl-pentyl)-2,5-dioxo-4-phenylamino-2,5-dihydro-1H-pyrrol-3-yl)-pyridinium chloride;
1-(1-dodecyl-2,5-dioxo-4-phenylamino-2,5-dihydro-1H-pyrrol-3-yl)-pyridinium chloride;
3-[2,5-dihydro-4-(1H-imidazol-1-yl)-1-methyl-2,5-dioxo-1H-pyrrol-3-yl]-1H-indole-1-carboxylic acid, 1,1-dimethylethyl ester;
3-(1H-imidazo[4,5-b]pyridin-1-yl)-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;
3-(1H-indol-3-yl)-1-methyl-4-(1H-pyrrolo[2,3-b]pyridin-1-yl)-1H-pyrrole-2,5-dione;
3-(1H-indol-3-yl)-1-methyl-4-(1-piperidinyl)-1H-pyrrole-2,5-dione;
3-[4-(diphenylmethyl)-1-piperazinyl]-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;
3-(1H-benzimidazol-1-yl)-4-(1H-indol-3-yl)-1-methyl-1H-pyrroIe-2,5-dione;
3-(1H-benzotriazol-1-yl)-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;
3-(1H-imidazol-1-yl)-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;
3-(1H-indol-1-yl)-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;
3-(1H-indazol-1-yl)-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;
3-[3-[(dimethylamino)methyl]-1H-indol-1-yl]-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione;
3-(1H-benzimidazol-1-yl)-4-(1H-indol-3-yl)-1H-pyrrole-2,5odone;
3-(1H-indol-1-yl)-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione, and;
3-(3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl)-4-(4-morpholinyl)-1H-pyrrole-2,5-dione.
Suitably, R2xe2x80x2xe2x80x3 is thienyl, phenyl, or phenyl substituted with one or more halogen groups.
Examples of R2xe2x80x2xe2x80x3 include phenyl, 3-thienyl, 2-thienyl, 4-chlorophenyl, and 2,4-dichlorophenyl.
Favourably, R2xe2x80x2xe2x80x3 is phenyl, 3-thienyl, 4-chlorophenyl, or 2,4-dichlorophenyl.
Suitably, R19xe2x80x2 is indolinyl, pyridinium halide, azabicyclooctanyl, or triazaspirodecanonyl.
Examples of R19xe2x80x2 include indolin-1-yl, 3-amino-1-pyridinium chloride, 2-methylindolin-1-yl, 1,3,3-trimethyl-6-azabicyclo[3,2,1]octan-6-yl, and 1-phenyl-1,3,8-triazaspiro-[4,5]-decan-4-one-8-yl.
Favourably, R19xe2x80x2 is indolin-1-yl, or 2-methylindolin-1-yl.
It is considered that the compounds of formula (ILxe2x80x2) are novel. Accordingly, the present invention also provides a compound of the above defined formula (ILxe2x80x2) or a derivative thereof.
Certain of the compounds of formula (I) may contain at least one chiral carbon, and hence they may exist in one or more stereoisomeric forms. The present invention encompasses all of the isomeric forms of the compounds of formula (I) whether as individual isomers or as mixtures of isomers, including racemates.
Alkyl groups referred to herein, including those forming part of other groups, include straight or branched chain alkyl groups containing up to six carbon atoms, said carbon atoms being optionally substituted with up to five, suitably up to three, groups selected from the list consisting of aryl, heterocyclyl, alkylthio, alkenylthio, alkynylthio. arylthio, heterocyclylthio, alkoxy, arylalkoxy, arylalkylthio, amino, mono- or di-alkylamino, cycloalkyl, cycloalkenyl, carboxy and esters thereof, phosphonic acid and esters thereof, mono- or dialkylaminosulphonyl, aminosulphonyl, cyano, alkylcarbonylamino, arylcarbonylamino, hydroxy, and halogen.
Alkenyl and alkynyl groups referred to herein include straight and branched chain alkenyl groups containing from two to six carbon atoms, said carbon atoms being optionally substituted with up to five, suitably up to three, groups including those substituents described hereinbefore for the alkyl group. Cycloalkyl and cycloalkenyl groups referred to herein include groups having between three and eight ring carbon atoms, which carbon atoms are optionally substituted with up to five, suitably up to three, groups including those substituents described hereinbefore for the alkyl group.
When used herein the term xe2x80x9carylxe2x80x9d includes phenyl and biphenyl groups, for example naphthyl, especially phenyl.
Suitably optional substituents for any aryl group include up to three substituents selected from the list consisting of halo, alkyl, alkenyl, substituted alkenyl arylalkyl alkoxy, alkoxyalkyl, haloalkyl, haloalkyloxy, hydroxy, hydroxyalkyl, nitro, amino, cyano, cyanoalkyl , mono- and di-N-alkylamino, acyl, acylamino, N-alkylacylamino, acyloxy, carboxy, carboxyalkyl, carboxyalkylcarbonyl, carboxyalkenyl, ketoalkylester, carbamoyl, carbamoylalkyl, mono- and di-N-alkylcarbamoyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxy, arylthio, aralkyloxy, aryloxycarbonyl, ureido, guanidino, morpholino, adamantyl, oxazolyl, aminosulphonyl, aikylaminosulphonyl, alkylthio, haloalkylthio, alkylsulphinyl, alkylsulphonyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, trityl, substituted trityl, mono- or bis-alkylphosphonate or mono- or bis-alkylphosphonateC1-6alkyl or any two adjacent substituents on the phenyl ring together with the carbon atoms to which they are attached form a carbocyclic ring or a heterocyclic ring.
When used herein the terms xe2x80x9cheterocyclylxe2x80x9d and xe2x80x9cheterocyclicxe2x80x9d suitably include. unless otherwise defined, aromatic and non-aromatic, single and fused, rings suitably containing up to four heteroatoms in each ring, each of which is selected from oxygen, nitrogen and sulphur, which rings, may be unsubstituted or substituted by, for example, up to three substituents. Each ring suitably has from 4 to 7, preferably 5 or 6, ring atoms. A fused heterocyclic ring system may include carbocyclic rings and need include only one heterocyclic ring.
Substituents for any heterocyclyl or heterocyclic group are suitably selected from halogen, alkyl, arylalkyl, alkoxy, alkoxyalkyl, haloalkyl, hydroxy, amino, mono- and di-N-alkyl-amino, acylamino, carboxy salts, carboxy esters, carbamoyl, mono- and di-N-alkylcarbonyl, aryloxycarbonyl, alkoxycarbonylalkyl, aryl, oxy groups, ureido, guanidino, sulphonylamino, aminosulphonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, heterocyclyl and heterocyclylalkyl.
When used herein xe2x80x98haloxe2x80x99 includes iodo, bromo, chloro or fluoro, especially chloro or fluoro.
Suitable derivatives of the compounds of the invention are pharmaceutically acceptable derivatives.
Suitable derivatives of the compounds of the invention include salts and solvates.
Suitable pharmaceutically acceptable derivatives include pharmaceutically acceptable salts and pharmaceutically acceptable solvates.
Suitable pharmaceutically acceptable salts include metal salts, such as for example aluminium, alkali metal salts such as lithium, sodium or potassium, alkaline earth metal salts such as calcium or magnesium and ammonium or substituted ammonium salts, for example those with lower alkylamines such as triethylamine, hydroxy alkylamines such as 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)-amine, cycloalkylamines such as bicyclohexylamine, or with procaine, dibenzylpiperidine, N-benzyl-xcex2-phenethylamine, dehydroabietylamine. N,Nxe2x80x2-bisdehydroabietylamnine, glucamine. N-methylglucamnine or bases of the pyridine type such as pyridine, collidine, quinine or quinoline.
Suitable pharrnaceutically acceptable salts also includes pharmaceutically acceptable acid addition salts, such as those provided by pharmaceutically acceptable inorganic acids or organic acids.
Suitable pharmaceutically acceptable acid addition salts provided by pharmaceutically acceptable inorganic acids includes the sulphate, nitrate, phosphate, borate, hydrochloride and hydrobromide and hydroiodide.
Suitable pharmaceutically acceptable acid addition salts provided by pharmaceutically acceptable organic acids includes the acetate, tartrate, maleate. fumarate, malonate, citrate, succinate, lactate, oxalate, benzoate, ascorbate, methanesulphonate, xcex1-keto glutarate and xcex1-glycerophosphate.
Suitable pharmaceutically acceptable solvates include hydrates.
For the avoidance of doubt when used herein the term xe2x80x9cdiabetesxe2x80x9d includes diabetes mellitus, especially Type 2-diabetes, and conditions associated with diabetes mellitus.
The term xe2x80x98conditions associated with diabetesxe2x80x99 includes those conditions associated with the pre-diabetic state, conditions associated with diabetes mellitus itself and complications associated with diabetes mellitus.
The term xe2x80x98conditions associated with the pre-diabetic statexe2x80x99 includes conditions such as insulin resistance, impaired glucose tolerance and hyperinsulinaemia
The term xe2x80x98conditions associated with diabetes mellitus itselfxe2x80x99 include hyperglycaemia insulin resistance and obesity. Further conditions associated with diabetes mellitus itself include hypertension and cardiovascular disease, especially atherosclerosis and conditions associated with insulin resistance. Conditions associated with insulin resistance include polycystic ovarian syndrome and steroid induced insulin resistance.
The term xe2x80x98complications associated with diabetes mellitusxe2x80x99 includes renal disease, especially renal disease associated with Type II diabetes, neuropathy and retinopathy. glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis and end stage renal disease.
A further aspect of the invention provides a process for the preparation of a compound of the invention, which process comprises reaction of a compound of formula (II): 
wherein R and R2 are as defined in formula (D and L is a leaving group, with a compound of formula (III): 
wherein R1 and R3 are as defined in formula (I); and thereafter, if required, carrying out one or more of the following optional steps:
(i) converting a compound of formula (I) to a further compound of formula (I);
(ii) removing any necessary protecting group;
(iii) preparing an appropriate derivative of the compound so formed.
Examples of suitable leaving groups, L, are chloro, bromo, triflate, and hydroxy.
The reaction between the compounds of formulae (II) and (III) is carried out in any suitable solvent, for example 1-methyl-2-pyrrolidinone, tetrahydrofuran, 0.880 ammonia, or methanol, under conventional amination conditions at any temperature providing a suitable rate of formation of the required product, generally an elevated temperature, over a suitable reaction time.
Suitable reaction temperatures include those in the range of 60xc2x0 C. to 220xc2x0 C. and, as appropriate, the reflux temperature of the solvent. When the compound of formula (III) is a weak nucleophile, then the reaction may be assisted by, for example, using temperatures at the upper end of this range, generating the anion of the compound of formula (III) in situ using, for example, sodium hydride, or by using a basic catalyst such as triethylamine. Conventional methods of heating also include the use of microwave heating devices, for example a microwave reactor, such as a 100 watt reactor.
The reaction products are isolated using conventional methods. Typically, the reaction mixture is cooled, the residue acidified and the products extracted using solvent extraction, suitably using an organic solvent.
The reaction products are purified by conventional methods, such as chromatography and trituration.
Crystalline product may be obtained by standard methods.
Crystalline product may be obtained by standard methods. In a preferred aspect, a solution of the compound of formula (II) and a compound of formula (III) in methanol is heated to reflux from between 1 to 4 days, then cooled and concentrated. The residue is then acidified with hydrochloric acid, and extracted with ethyl acetate. The organic extracts are then washed with water, brine, dried with anhydrous magnesium sulphate, and the solvent is removed. The product is then purified by standard methods such as trituratlon or chromatography, on silica gel, to afford the desired compound.
The above mentioned conversion of a compound of formula (I) into another compound of formula (I) includes any conversion which may be effected using conventional procedures, but in particular the said conversions include any combination of:
(i) converting one group R into another group R;
(ii) converting one group R3 into another group R3;
(iii) converting one group R10 into another group R10, and;
(iv) converting one group R11 into another group R11.
The above mentioned conversions (i) to (iv) may be carried out using any appropriate method under conditions determined by the particular groups chosen.
Thus, suitable conversions of one group R into another group R, as in conversion (i), include:
(a) converting a group R which represents hydrogen into a group R which represents an alkyl or arylalkyl group; such conversion may be carried out using an appropriate conventional alkylation procedure, for example treating an appropriately protected compound of formula (I) with an alkylating agent; and
(b) converting a group R which represents an alkyl group into a group R where R represents hydrogen; such conversion may be carried out using an appropriate dealkylation procedure, for example treating an appropriately protected compound of formula (I) with aqueous base followed by ammrnonium hydroxide.
Suitable conversions of one group NR1R3 into another group NR1R3, as in conversion (ii), include:
converting a group NR1R3 which represents arylamino into another group NR1R3 which represents alkylamino: such conversion may be carried out using an appropriate conventional procedure, for example treating an appropriately protected compound of formula (I) with an alkylamine.
Suitable conversions of one group R10 into another group R10, as in conversion (iii), include:
(a) converting a group R10 which represents nitro into a group R10 which represents amino, such conversion may be carried out using a conventional reduction procedure, for example hydrogenating an appropriately protected compound of formula (I);
(b) converting a group R10 which represents nitro into a group R10 which represents acetylamino, such conversion may be carried out using an appropriate conventional reductive acylation procedure, for example hydrogenating an appropriately protected compound of formula (I) followed by acylation of the resultant amino group with an acylating agent;
(c) converting a group R10 which represents amino into a group R10 which represents a substituted urea, such conversion may be carried out using an appropriate conventional amidation procedure, for example treating an appropriately protected compound of formula (I) with an appropriately substituted isocyanate;
(d) converting a group R10 which represents amino into a group R10 which represents acylamino, such conversion may be carried out using an appropriate conventional acylation procedure, for example treating an appropriately protected compound of formula (I) with an acylating agent or treating an appropriately protected compound of formula (I) with a suitable carboxylic acid in the presence of activating agents such as a mixture of 1-hydroxybenrotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, and;
(e) converting a group R10 which represents iodo into a group R10 which represents alkoxycarbonyl, such conversion may be carried out using an appropriate procedure, for example treating an appropriately protected compound of formula (I) with carbon monoxide and methanol in the presence of a palladium(0) complex.
Suitable conversions of one group R11 into another group R11, as in conversion (iv), include:
(a) converting a group R11 which represents a t-BOC-protected amino group into a group R11 which represents amino, such conversion may be carried out using an appropriate conventional deprotection procedure, for example deprotecting a t-BOC-protected compound of formula (I) with trifluoroacetic acid;
(b) converting a group R11 which represents a carboxylic acid group into a group R11 which represents an amide group, such conversion may be carried out using an appropriate conventional procedure, for example treating an appropriately protected compound of formula (I) with an amine in the presence of suitable activating agents such as a mixture of 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide: and
(c) converting a group R11 which represents alkoxycarbonyl into a group R11 which represents carbamoyl, such conversion may be carried out using an appropriate conventional procedure, for example treating an appropriately protected compound of formula (I) with methanolic ammonia solution followed by aqueous ammonia.
The above mentioned conversions may as appropriate be carried out on any of the intermediate compounds mentioned herein.
Suitable protecting groups in any of the above mentioned reactions are those used conventionally in the art The methods of formation and removal of such protecting groups are those conventional methods appropriate to the molecule being protected. Thus for example a benzyloxy group may be prepared by treatment of the appropriate compound with a benzyl halide, such as benzyl bromide, and thereafter, if required, the benzyl group may be conveniently removed using catalytic hydrogenation or a mild ether cleavage reagent such as trimethylsilyl iodide or boron tribromide.
Where appropriate individual isomeric forms of the compounds of formula (I) may be prepared as individual isomers using conventional procedures.
The absolute stereochemistry of compounds mav be determined using conventional methods, such as X-ray crystallography.
The derivatives of the compounds of formula (I), including salts and/or solvates, may be prepared and isolated according to conventional procedures.
The compounds of formula (II) are known compounds orthey may be prepared using methods analogous to those used to prepare such compounds such as those described in International Patent Application. Publication Number WO97/34890 and Wiley. R. H. and Slaymaker. S. C. J. Am. Chem. Soc. (80) 1385 (1958). The compounds of formula (II) may be inter-converted in an analogous manner to the above mentioned inter-conversions of the compounds of formula (I).
The compounds of formula (III) are either commercially available, or are reported in the chemical literature, or are prepared by analogy with known conventional literature procedures, for example those disclosed in Chem. Ber., 1892, 25, 2977, J. Amer. Chem. Soc. 1948, 70, 4174-4177, Synthesis 1977, 859, J. Med. Chem., 1994, 37, 3956, Synthesis 1994, 1413, and Tetrahedron, 1991, 47, 2661, or in standard reference texts of synthetic methodology such as J. March, Advanced Organic Chemistry, 3rd Edition (1985), Wiley Interscience.
As stated above, the compounds of formula (I), or pharmnaceutically acceptable derivatives thereof, are indicated to be useful as inhibitors of glycogen synthase kinase-3.
Thus the present invention further provides a compound of formula (I), or a pharmaceutically acceptable derivative thereof, for use as an inhibitor of glycogen synthase kinase-3, and especially for use in the treatment of conditions associated with a need for the inhibition of glycogen synthase kinase-3, such as diabetes, especially Type 2 diabetes, dementias, such as Alzheimer""s disease and manic depression.
The present invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable derivative thereof, for the manufacture of a medicament for the treatment of conditions associated with a need for the inhibition of glycogen synthase kinase-3, such as diabetes, especially Type 2 diabetes, dementias, such as Alzheimer""s disease and manic depression.
As indicated above, formula (I) comprises a sub-group of compounds of formula (IA). In a further aspect of this invention, there is provided a compound of formula (IA), or a pharmaceutically acceptable derivative thereof, for use as an active therapeutic substance.
Accordingly, the invention also provides a pharmaceutical composition which comprises a compound of formula (IA), or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier.
Preferably, the compounds of formula (I), or pharmaceutically acceptable derivatives thereof are administered as pharmaceutically acceptable compositions.
As indicated above it is considered that GSK-3 inhibitors per se are potentially useful in the treatment and/or prophylaxis of mood disorders, such as schizophrenia. neurotraumatic diseases, such as acute stroke, and for the treatment and/or prophylaxis of cancer and hair loss.
Accordingly, in a further aspect the invention provides a method for the treatment and/or prophylaxis of mood disorders, such as schizophrenia, in a mammal, such as a human, which method comprises the administration of a pharmaceutically acceptable amount of a GSK-3 inhibitor.
The invention also provides a method for the treatment and/or prophylaxis of neurotraumatic diseases in a maammal, such as a human, which method comprises the administration of a pharmaceutically acceptable amount of a GSK-3 inhibitor.
Neurotraumatic diseases include both open or penetrating head trauma, such as caused by surgery, or a closed head trauma injury, such as caused by an injury to the head region ischaemic stroke, including acute stroke, particularly to the brain area transient ischaemic attacks following coronary by-pass and cognitive decline following other transient ischaemic conditions.
Further provided is a method for the treatment and/or prophylaxis of cancer, in a mammal, such as a human, which method comprises the administration of a pharmaceutically acceptable amount of a GSK-3 inhibitor.
In addition there is provided a method for the treatment and/or prophylaxis of hair-loss, in a mammal, such as a human, which method comprises the administration of a pharmaceutically acceptable amount of a GSK-3 inhibitor.
Thus, the invention also provides the use of a GSK-3 inhibitor for the manufacture of a medicament for the treatment and/or prophylaxis of mood disorders, schizophrenia, neurotraumatic diseases, cancer or hair-loss.
A suitable GSK-3 inhibitor is a compound of formula (I) or a pharmaceutically acceptable derivative thereof.
The active compounds are usually administered as the sole medicament agent but they may be administered in combination with other medicament agents as dictated by the severity and type of disease being treated. For example in the treatment of diabetes, especially Type 2 diabetes, a compound of formula (I), or a pharmaceutically acceptable derivative thereof, may be used in combination with other medicament agents, especially antidiabetic agents such as insulin secretagogues, especially sulphonylureas, insulin sensitisers, especially glitazone insulin sensitisers (for example thiazolidinediones), or with biguanides or alpha glucosidase inhibitors or the compound of formula (I), or a pharmaceutically acceptable derivative thereof, may be administered in combination with insulin.
The said combination comprises co-administration of a compound of formula (I), or a pharmaceutically acceptable derivative thereof, and an additional medicament agent or the sequential administration of a compound of formula (I), or a pharmaceutically acceptable derivative thereof, and the additional medicament agent.
Co-administration includes administration of a pharmaceutical composition which contains both a compound of formula (I), or a pharmaceutically acceptable derivative thereof, and the additional medicament agent or the essentially simultaneous administration of separate pharmaceutical compositions of a compound of formula (I), or a pharmaceutically acceptable derivative thereof, and the additional medicament agent
The compositions of the invention are preferably adapted for oral administration. However, they may be adapted for other modes of administration.
The compositions may be in the form of tablets, capsules, powders, granules, lozenges, suppositories, reconstitutable powders, or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
In order to obtain consistency of administration it is preferred that a composition of the invention is in the form of a unit dose.
Preferably the composition are in unit dosage form. A unit dose will generally contain from 0.1 to 1000 mg of the active compound.
Generally an effective administered amount of a compound of the invention will depend on the relative efficacy of the compound chosen, the severity of the disorder being treated and the weight of the sufferer. However, active compounds will typically be administered once or more times a day for example 2, 3 or 4 times daily, with typical total daily doses in the range of from 0.1 to 800 mg/kg/day.
Suitable dose forms for oral administration may be tablets and capsules and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine, tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulphate.
The solid oral compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are of course conventional in the art. The tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.
Oral liquid preparations may be in the form of, for example, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats: emulsifying agents, for example lecithin, sorbitan monooleate, or acacia: non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol: preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring agents.
For parenteral administration, fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, and, depending on the concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and scaling. Advantageously, adjuvants such as a local anaesthetic, a preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilization cannot be accomplished by filtration. The compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
The formulations mentioned herein are carried out using standard methods such as those described or referred to in reference texts such as the British and US Pharmacopoeias, Remington""s Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) or the above mentioned publications.
Suitable methods for preparing and suitable unit dosages for the additional medicament agent, such as the antidiabetic agent mentioned herein include those methods and dosages described or referred to in the above mentioned reference texts.
Types of GSK-3 assay used to test the compounds of the invention include the following:
Type 1: The GSK-3 specific peptide used in this assay was derived from the phosphorylation site of glycogen synthase and its sequence is: YRRAAVPPSPSLSRHSSPHQ(S)EDEEE. (S) is pre-phosphorylated as is glycogen synthase in vivo and the three consensus sites for GSK-3 specific phosphorylation are underlined. The buffer used to make up the glycogen synthase peptide and [xcex3-33p] ATP consisted of MOPS 25 mM, EDTA 0.2 mM, MgAcetate 10 mM, Tween-20 0.01% and mercaptoethanol 7.5 mM at pH 7.00.
The compounds were dissolved in dimethyl sulphoxide (DMSO) to a final concentration of 100 mM. Various concentrations were made up in DMSO and mixed with the substrate (GSK-3 peptide) solution (to a final concentration 20 xcexcM) described in the above section along with rabbit or human GSK-3xcex1 and GSK-3xcex2 (final concentration 0.5 U/ml enzyme). The reactions were initiated with the addition of [xcex3-33P] ATP (500 cpm/pmole) spiked into a mixture of ATP (final concentration of 10 xcexcM). After 30 min at room temperature the reaction was terminated by the additionof 10 xcexcl of H3PO4/0.01%Tween-20 (2,5%). A volume (10 xcexcl) of the mixture was spotted onto P-30 phosphocellulose paper (Wallac and Berthold, EGandG Instruments Ltd, Milton Keynes). The paper was washed four times in H3PO4 (0.5%), 2 mins for each wash, air dried and the radioactive phosphate incorporated into the synthetic glycogen synthase peptide, which binds to the P-30 phosphocellulose paper, was counted in a Wallac microbeta scintillation counter.
Analysis of Data: Values for IC50 for each inhibitor were calculated by fitting a four-parameter logistic curve to the model: cpm=lower+(upper-lower)/(1+(concentration/IC50)slope).
Type 2: This protocol is based on the ability of the kinase to phosphorylate a biotinylated 26 mer peptide, sequence of which derived from the phosphorylation site of glycogen synthase and its sequence is Biot- YRRAAVPPSPSLSRHSSPHQ(S)EDEEE, with (S) is a pre-phosphorylated serine as is glycogen synthase in vivo and the three consensus sites for GSK-3 specific phosphorylation are underlined. The phosphorylated biotinylated peptide is then captured onto strrptavidin coated SPA beads (Amersham Technology), where the signal from the 33P is amplified via the scintillant contained in the beads.
The kinase was assayed at a concentration of 10 nM final in 25 mM MOPS buffer, pH 7.0 containing 0.01% Tween-20, 7.5 mM 2-mercaptoethanol, 10 mM Magnesium acetate. and 10 uM [xcex3-33p]-ATP. After 60 minutes incubation at room temperature, the reaction was stopped by addition of 50 mM EDTA solution containing the Streptavidin coated SPA beads to give a final 0.5 mgs of beads per assay well in a 384 microtiter plate format.
10 mM stock solutions of the compounds of the invention in 100% DMSO are generated as a first step in the screening process. The second step involves the creation of dose response plates where these compounds are diluted across the plate where the final low and high concentrations are to be 0.008 and 10 uM final in the kinase assay. The third step involves the creation of the assay plates. This is achieved by transferring the compounds from four 96 dose response plates to one 384 assay plate on the Robocon Robolab system. The fourth step is to perform the assay as described and count the resulting plates in the Trilux (Wallac 1450 microbeta liquid scintillation and luminescence counter). The final step is data acquisition and analysis where IC50 values are generated for each compound in duplicate by fitting a four parameter logistic curve to the model: cpm=lower+(upper-lower)/(1+(concentration/IC50)slope) in a batch manner.
The most potent compounds of the present invention show IC50 values in the range of from between 10 to 100 nM.
No adverse toxicological effects are expected for the compounds of the invention when administered in accordance with the invention.